18 years old male.

Previous illness:
1 year old: Roseola.
4 years old: Salmonellosis.
6 years old: Varicella.
18 years old: Surgery in endoscopy due to left varicocele.

Clinical History:
4 months ago hospitalization following epigastric abdominal pain, at times postprandial, from 2 weeks linked to ingravescent lack of appetite and weight loss (3 kgs in a month). During hospitalization the most significant medical tests carried out were:
- Ultrasound scan and MR cholangiography with evidence of bile ducts dilatation.
- Endoscopy of the bowel with evidence of terminal ileitis and colitis with histological diagnosis of Crohn’s disease.
- Hepatic biopsy with evidence of an overlap syndrome picture (cholangitis/hepatitis).
- Lab examinations with finding of elevate levels of IgG (2937) and positive results of C-ANCA antibodies.
Therapy started with Cortisone 50 mg and Azathioprine 100 mg.

Second hospitalization, 1 month later, following appearance of arising colics, difficult to treat with pain medications, high body temperature and increase in inflammation ratings, symptoms consistent with picture of infective cholangitis. Therefore, the picture was resolved with antibiotic therapy and with carrying out a papillotomy by means of ERCP. Discharged under antibiotic therapy with Ciprofloxacin, Cortisone and Azathioprine.

Third hospitalization, 3 days after discharge from previous hospitalization, following arising colics with progressive ultrasound scan dilatation of bile ducts and evidence of dropsy of the gallbladder. Moreover, 48 hours following hospitalization, amylase increase (600 UI/l) was detected. The IgG4 dosage (18 mg/dl) was within normal limits, excluding a possible autoimmune hepatitis/pancreatitis syndrome.
ERCP performed with dilatation and cleaning of the common bile duct that involved the spillage of corpuscular material and bile with purulent appearance bringing about a fast improvement of symptomatology and a rapid reduction in the amylase values.
Later on, laparoscopic cholecystectomy was carried out. During postsurgery, after a short period of wellness, the patient suffered from an abdominal pain. Reappearance interpreted, at the beginning, as a light pancreatitis (treated with antibiotic therapy). Subsequently, persisting painful crises were observed despite blood tests substantial stability.
Therefore, a MR cholangiography was carried out (images enclosed on CD) that has revealed an appearance of intra- and extrahepatic bile duct dilatation, evident also at common bile duct level where the picture seems revealing a relevant stenosis: “Intrahepatic bile ducts with clear wall irregularity and with minimal stenosis followed by dilatations in a picture to be related to the base pathology. Irregularity at the extrahepatic bile ducts and at the common bile duct level too…, the common bile duct distal region appears moderately reduced in diameter, also in papillary region, also as a result of papillotomy.”
In the light of the aforesaid, a biliary stent was placed during ERCP in order to guarantee bile ducts patency. The clinical picture, after surgery, was stable with occasional presence of pains involving mainly the right hypochondrium without any characteristics of biliary colics. At discharge, blood tests with evidence of improvement of the hepatic cytolisys index (AST 28, ALT 38) with still elevated values of gammaGt (197) and APC 2.02 mg/dl probably linked to the inflammatory pathology rather than to an infective event. Discharge with indication to follow a therapy with Deltacortene to scale down the Azathioprine and antibiotic therapy with Augmentin.

Fourth hospitalization, 1 month later, in gastroenterology department for clinical test: The patient reported slight painful crisis in epigastric region; at examinations APC negativization (0.59) and a further reduction in GGTs with transaminase substantially stable. Therefore, the therapy with Amoxicillin + Clavulanic Acid was suspended and Metronidazole 250 mg was prescribed 3 times a day every other week.

Fifth hospitalization during the same month, following an episode of infective cholangitis with blood tests that showed transaminase on the increase (ALT 248, AST 114, GGT 281) with leukocytosis (WBCs 13,000, Nuetrophyls 88%, Lymphocytes 7.9%) and elevated APC (4.48). Therapy started with Augmentin (1 g x 3 times a day) for 7 days and then end. At the end of the 7 days, preventive treatment prescribed with Cotrimoxazole (tablet 160+800) 1 tablet twice a day.

Sixth hospitalization, 2 weeks after the privious one, following epigastric pain and nausea occurred after 1 day from Augmentin interruption and 1 day after the beginning of therapy with Cotrimoxazole.
The most significant lab examinations at admission: CRP=1.92 mg/dl; GGT 129 U/L; AST= 29 u/l, ALT=97 U/L.
Abdomen ultrasound scan with evidence of common bile duct dilatation. “Dilatation of the proximal and medial segment of the common bile duct, with diameter up to 10 mm, in whose context binary images are appreciated referable to the well-known stent. A moderate ectasia of intrahepatic bile ducts is connected, in particular in the left parts.”
To treat the severe painful symptomatology, a therapy with Keterolac 90 mg in 250 cc in continuous infusion was started
Because of the increase in the inflammation ratings and in the dilatation of the common bile duct at the abdominal ultrasound scan, supposing an occlusion of the biliary stent with overlapped cholangitis, an antibiotic therapy has been started with Meropenem 1 g x 3 and an ERCP was carried out.
ERCP didn’t show any materials obstructing the stent. Biliary washing was within normal limits.
Therapy prescribed at home:
Augmentin (1 g x 3); Ciproxin (500 mg x 2); Folina 5 mg (1 tablet every other day); Deltacortene (25 mg daily); Azathioprine (100 mg daily); Lansoprazole (30 mg daily); Ursodesossicolic Acid (300 mg 3 times a day).

During this latest hospitalization the young patient is sent for second opinion to hospitalization in different hepatology and gastroenterology unit. Medical tests carried out confirmed what already known from the first hospitalization and the current therapy is confirmed.

Last hospitalization was due to reappeared epigastric pain in the attempt to interrupt the antibiotic therapy. During hospitalization, bringing back the antibiotic therapy, the situation progressively improved and allowed his discharge with the following therapy:
Augmentin (1 g x 3); Ciproxin (500 mg x 2); Folina 5 mg (1 tablet every other day); Deltacortene (15 mg daily); Azathioprine (100 mg daily); Lansoprazole (30 mg daily); Ursodesossicolic Acid (300 mg 4 times a day).
 

1) Do you confirm the therapy?
I have reviewed the case in detail but unfortunately I have not been able to see the report of the CT scan or colonoscopy. But, based on my experience we are dealing with Primary Sclerosing Colangitis (PSC) with either Crohn’s disease (CD) or more likely Ulcerative colitis (UC). MRCP based bile duct dilation along with picture of inflammatory bowel disease confirms the diagnosis. I would like to review the histology, but in any case both CD and UC can be associated with PSC. Autoimmune hepatitis can also be seen in this condition particularly in patients that are young. We see an association of pANCA with UC or a CD variant called pANCA positive Crohn’s disease which primarily affects the colon. ASCA IgA and ASCA IgG may help us distinguish CD from UC.
I do have some concerns about the therapy. We try our very best not to insert biliary stents in PSC patients. We conservatively manage patients (IV antibiotics, IV fluids and steroids). Stents can lead to recurrent infections in immune suppressed patient. Recurrent attacks of colangitis will lead to stricture formation. Currently, I suggest the following:
a) Antibiotic Rx (long term, on rotation basis), start with ½ dose Augmentin (875 md a day), next month take ½ dose Bactrim (1 DS a day) and third month take Ciprofloxin 500 mg a day. After the end of 3 months, please restart the cycle of antibiotics. This approach will prevent acute colangitis flares and while we dial up the immune suppression.
b) Switch Deltacortene with Entocort (Budesonide) 9 mg a day for 3 months. This drug is effective in autoimmune hepatitis but does not cause systemic steroid side effects
c) Azathioprine (AZA) is a good choice and the patient seems to be tolerating it well. But 100 mg dose may not be correct. Please check therapeutic metabolite of AZA, 6TGN and hepatotoxic agent 6MMPN. Based on these results, adjust dose of AZA. Majority of patients require 2.5 mg per Kg body weight. So if the patient is 50 kg, his dose will be 125 mg AZA, daily. Once 6TGN is in therapeutic range I wait 6 weeks or so to assess response. Remember, AZA is at best 40% efficacious, which means it will be ineffective in more than half of the patients treated.
d) If AZA is infective, or if the patient continues to progress we would consider remicade 5mg a kg at weeks 0, 2 and 6. Since he is only 18 years old, I would suggest remicade monotherapy as AZA plus Remicade increases the risk of hepato-splenic T cell lymphoma in the young. However, Remicade should be given in conjunction with Entocort and antibiotics. Suggest using a clinical score to assess his disease score before and after remicade induction. If results are favorable, he can be put in a Remicade maintenance program, where the patient receives remicade 1 dose every 6-8 weeks. Results with Remicade are significantly better than AZA both with simple efficacy score but also in terms of lifestyle. It is important that he completes school and is able to achieve his career goals.

2) Any alternative and/or experimental treatment for a complete recovery?
In immune disorders, there is no concept of complete recovery. There is a good chance of bringing him in sustained disease remission by treating him with lifelong immune therapy. Risks a lifelong immune therapy is low compared to the benefits. As long as he has good medical support he should be able to handle immune suppression and continue with his life, career, marriage and even having children.
After anti TNF treatment with remicade, the patient has 2 other alternatives within this class of drug. These include humira and cimzia. Both these drugs are self injectable and less imuunogenic than remicade. Anti integrin approach with natalizumab (Tysabri) is also approve for anti TNF failures. Anti IL12/23 antibody or ustekinumab is currently under clinical trials.

3) What is your opinion on the possible use of steam cells in this case?
Stem cell therapy can be very effective as stem cells isolated from patient’s blood or bone marrow can be re-injected. After re-injection, these cells home to sites of inflammation and can cause healing. Unfortunately, we have no data on these studies. Major clinical trials in the USA had to be stopped because of high placebo effect. We were participating in these trials but had to stop. My opinion is that the patient needs to be treated by anti-TNF approach first before pursuing experimental therapy.

4) Can you advise Italian and international centers of excellence and their relevant reference specialists?
I know Dr Silvio Danese who was in Rome and maybe now in Milan, if you give me permission, I can email him and find you a doctor who is close to your home and is familiar with PSC in CD.

5)In this case, can you express your opinion on the Imperial College of London in which some doctors (Prof. Nagy Habib, Prof. F. Dazzi) use a stem cells therapy?
I am not familiar with UK scene, but at this stage, any doctor who has training in IBD should be able to help the patient.

6) Prognosis?
The patient is at risk for liver transplant. Young patients that have recurrent PSC with minimal bowel symptoms are usually not effectively immune suppressed and end up developing strictures, cirrhosis and bile duct cancer. After transplant, the immune suppression is mandatory and usually help luminal CD (both large and small intestine). If rotating antibiotics plus immune suppression is effective, he will do very well. He will need to be followed at a center that has experience in such diseases. With the advances in genetics, immune and stem cell therapy we are anticipating even bigger breakthroughs in medical treatment. Therefore, if can help him pull through this recurrent colangitis phase, we can be optimistic about his case.
 

A 72 years old female.
8 years ago the patient was diagnosed with adenocarcinoma of the sigma with liver metastasis. She underwent sigmoidectomy and was then treated with chemotherapy under the FOLFIRI protocol, with substantial regression of the liver metastasis.
9 months after the begininig of the chemotherapy she underwent surgical excision of some of the liver metastasis and radio-frequency ablation of additional metastasis. During the surgical procedure, a catheter was implanted in the hepatic artery.
Following surgery, she received systemic chemotherapy under the FORFOLI protocol, combined with local intra arterial chemotherapy. An half a year after the chemotherpy the treatmentet was halted on for technical reasons.
During follow-up, progression of the liver metastasis was noted and treatment with FOLFOX and AVASTIN was administered one year after the ending of the previous chemotherapy cycle .

3 years after the diagnosis, the patient underwent partial hepatectomy and removal of the remaining liver metastasis. Pathological examination of the excised specimens showed only fibrosis, without histological evidence of malignancy.
8 months later, CEA levels were elevated and PET-CT demonstrated liver metastasis progression. Treatment with OXYPLATIN was initiated but soon withheld due to severe allergic reaction. Eventually she was treated with DEGRAMON and ERBITUX which was halted later to her request.

1.5 years later, CEA elevated to 70 and CT demonstrated enlargement of a liver metastasis. Treatment with XELODA was initiated with stabilization of her disease, up until 10 months later, where further progression was noted by elevation of CEA levels to 140 and enlargement of liver metastasis by PET-CT.
3 months later Re-treatment with FOLFIRI was initiated with stabilization of her disease for almost one year, where further progression was noted by PET-CT.

An year and a half later, treatment with Irinotecan and Erbitux was initiated with partial remission up until the last 2 months where elevated CEA (315) and PET-CT demonstrated progression of her disease.
Re-treatment with XELODA was administered but soon withheld due to 3rd level toxicity.
 

The patient is a 72 year old female with history of metastatic colorectal cancer for past 8 years on continuous chemotherapy with some treatment break, now with progressive disease after all standard treatments.
This consult was based on the records provided only. No radiographs or pathology were reviewed at our center.
To begin, based on the summary of the history provided, I believe this patient has been managed very appropriately over the years. She has had the appropriate level of aggressiveness balanced with quality of life considerations. There are 7 approved drugs in 5 classes for metastatic colorectal cancer. Unfortunately, there are a growing number of patients that eventually exhaust these options and have no other standard therapies.

At this point, I would discuss with the patient 2 options.
-First would be best supportive care only. The advantage of this option would be maximizing quality of life without risking toxicities of further treatment. Further treatment would be a clinical trial with agents without definitive data yet to know if the agent would change the natural history of this type of cancer and thus the risk of a trial medication is potential toxicity where it is possible there won’t be efficacy in any patient, let alone this patient.

-Second option would be a clinical trial. I would group trials for this patient in 2 forms:
1. First would be a trial specific to colorectal cancer. Those trials may be specific to colorectal cancer because early data is suggestive of potential benefit in a limited number of colorectal cancer patients and thus the drug is being tried in a larger population of colorectal cancer. Or it may be a drug that is being tested in colorectal cancer because preclinical data are supportive for this disease type but there are no human data yet that the preclinical data will translate to humans.
2. Second type of trial would be a phase I trial for an experimental agent that is being tested in many cancer types and the goal of the trial is to determine tolerance of the drug as well as potential tumor subtypes that may benefit.

One could look on www.clinicaltrials.gov for options elsewhere though I would state I don’t know of a trial specific to colorectal cancer that I have knowledge is definitely promising – but we would not know until it is tested. We do have an active phase I program run by a different group of physicians. At any given time, they have about 10-15 active phase I trials – some agents may make more sense for colorectal cancer but availability and choice of drug will require a consultation with them and if the patient would join a phase I trial here, all treatment needs to occur here. Other major academic centers also have phase I programs that may be closer to home for this patient.

In conclusion, I concur with the management for this patient to date. There are no standard therapies I would offer at this time – the option would be consideration of a phase I trial.
 

52 years old male, that following the onset of algic symptomatology of the spine carried out the following lumbosacral spine diagnostic tests:
- X-ray of lumbosacral spine - 2 projections -
“slight left lumbar convex scoliotic attitude on wide scale without coarse rotation of the metamers on their vertical axis. Attendant diffuse moderate signs of arthrosis, more evident at the lumbosacral passage, marked by sclerosis of the articular facets, sharpening of the profiles and tendency to marginal osteophytosis. Moderate reduction of size of the L5-S1 disk space".

- Lumbosacral Spine NMR -
"Small osteoangioma in the L1 soma. Diffuse arthritic abnormalities at the somatic marginal branches and articular facets. The spine channel size is within normal limits. Subligament median disk hernia at L2-L3 that modestly impresses the dural sac in the center. Small median disk hernia at L3-L4 that modestly impresses the dural sac in the center. The protrusion also pushes into the foramen, which also reduces the epidural fat around the roots of L3. Posterior disk protrusion at L4-L5 and more evident at the intra- and extra-foramen site, with slight impression on the dural sac and reduction of the epidural fat around the roots of L4 that appear reached, but not grossly compressed. Posterior disc protrusion at L5-S1 and intra- and extra-foramen more evident to the right, where the root of L5 arrives from this side. Radicular arachnoid cysts at S1-S2 in right paramedian area. Cone and cauda normal. Schmorl nodules in the somatic plates of L4 and in the inferior somatic plate of L1."

The patient was then sent to physiatric and neurosurgical specialist assessments, the findings of which are reported:
- Physiatric examination:
Objective examination: no significant deviations of the spine. Motility uncompromised. No signs of spinal pain. Strength and sensitivity uncompromised. DIM at lumbar level.
Conclusions -> Postural back pain, so we recommend: Cycle of muscle relaxant massotherapy (10 sessions); Expose 100 mg 1 tab in the evening for 5 days; at least two weeks of working out dorsal, abdominal and gluteal muscles at the gym before resuming sports activity (golf).

- Neurosurgical examination:
The specialist finds nothing neurological in nature; he also refers to the NMR carried out (reported above) that, in his opinion, shows nothing particular unless for some moderate protrusions and two vertebra angiomas, which have no pathological meaning.
Conclusions -> evidence of dorsal paravertebral contracture, so local ice and massotherapy are recommended.

The patient is a 52 year old man with back pain. I am not given a description of the character or location of the pain, nor is there any mention of radicular symptoms in the legs.

Plain x-rays were read as showing mild left scoliosis without rotation. There was sclerosis at the L5S1 facets, marginal osteophytes, and decrease in the height of the L5S1 disc space.
The MRI scan, which I read, showed mild central disc bulges at L23 and L34 without significant impingement on the dural sac. There is a mild central and left-sided disc bulge at L45 which slightly narrows the left L4 foramen. The conus medullaris and the cauda equina are normal. There are Schmorl's nodes at L4 and L1, and there is a hemangioma in the body of L1. There is a Tarlov cyst (arachnoid cyst) on the right S2 nerve root.
The physiatrist found normal strength and sensation and no spine tenderness. The neurosurgeon found "nothing neurological", which I take to mean no symptoms or physical signs of radiculopathy.

The diagnosis is myofascial back pain, which probably relates to the x-ray and MRI findings of mild disc degeneration. These findings, mild disc bulging, loss of L5S1 disc height, and Schmorl's nodes, are normal for the patient's age, and they do not correlate well with back pain. I do not see any scoliosis on the scout films for the MRI, so I do not believe that what was seen on the plain films (probably taken supine) is significant. Hemangiomas in the bodies of vertebrae are very common in the population. They are benign, do not increase in size, do not spread, and do not cause pain. Arachnoid (Tarlov) cysts in the sacral spine are also common and do not cause symptoms except in very rare circumstances.

Given the lack of major structural problems in the bones or discs, the pain can be expected to spontaneously abate and disappear with time. I agree with the physiatrist's prescription for physical therapy aimed at core strengthening, lower extremity stretching, and massage. These exercises, and attention to achieving and maintaining normal weight (body mass index), with gradual return to customary activity and sports, are the basis of prevention of future episodes of pain. I do not find any indication for injections or for surgery with this history and these MRI findings.

35 years old male. No significant notable pathology in anamnesis.
3 years ago, symptomatic beginning of lumbar pain when the patient, spending a lot of time seated in his office, complained of pain in his back when standing up from the chair.
Following X-ray test and lumbar spine MNR a disc herniation was diagnosed, which in those days was not associated with lower limbs paresthesias.
The MNR medical report: “Paramedian median protrusion with right prevalence occurs at the L4-L5 intersomatic space, with moderate pressure effects on the dural sac and it slightly migrates upwards involving the armpit-shaped area of the right L4 root. No alterations of the spongious bone in the STIR sequences referable to edema. Spinal canal normal for morphology and dimensions. Degenerative notes involving L3-L4 and L4-L5 intervertebral discs with strong dystrophic reaction of the opposed endplates and depression of L4 anterior-superior limit due to disc intraspongious herniation. Signs of spondylosis. Spine straightening due to normal curvature loss.”

Later on, disorders showed up sporadically, therefore the patient didn’t pay particular attention to them.
On the contrary, about 15 days ago, as a result of backache recurrence, an injection of Voltaren and Muscoril was needed following which the pains completely disappeared.

The patient, however, decided to carry out diagnostic deepening performing a new lumbosacral magnetic resonance and an electromyographic examination, the reports of which are the following ones:
-  Lumbosacral magnetic resonance: “Presence of spondylosis phenomena more evident at the level of the distal segment of the lumbosacral spine. The spinal canal dimensions are within normal limits. Intersomatic discs L3-L4 and L4-L5 show reduced signal in T2 due to dehydration phenomena. At L4-L5 level, evidence of localized discal herniation in right median and lateral area that causes compression on the ventral dural sac. At L3-L4 level, detection of median protrusion of the intervertebral disc more towards left, resulting in moderate impression on the dural sac. Presence of Schmorl’s node at the level of L4 upper somatic limit on the anterior side. Normal the remaining intersomatic spaces of the spine segment examined”.

- Lower limbs EMG: "The examination has revealed signs of chronic neurogenic damage, without any current denervations, with right L5-(S1) distribution.”

On completion of the clinical picture, the patient carried out another lumbosacral spine X-ray recently which simply revealed “disc impressions involving the endplates analyzed.”
 

To summarize the history, the patient is a 35 years old office worker, healthy otherwise, who started having low back pain 3 years ago. The pain was related to history of prolonged sitting with getting up from the chair. At that time the pain was axial only.
The ordered lumbar MRI at that time showed spondylosis and degenerative disc disease mostly in the L3-4 and L4-5 segments with right L4-5 disc herniation.
The pain was persisting on an on and off basis until four weeks ago, when the axial low back pain increased with lower extremities radiation, parasthesias and tingling. The pain is constant, fluctuating at a 1-8/10 VAS level. The pain increases with prolonged sitting and getting up from the chair. It improves in supine position and resolves with am injection of Voltaren with Muscoril.
No bowel or bladder symptoms. The patient is still able to function and continue attending work.
The physical examination findings reported, are limited to lumbar muscles tenderness.
The lumbar MRI, that was repeated, was consistent with spondylosis and degenerative disc disease. Worsening disc herniation both at L3-4 with left side herniation and L4-5 with right disc herniation (reports reviewed/images not available).
An EMG/NCS later, showed chronic signs of denervation in right L5 (S1) segment.

ASSESSMENT: A 35 year old male with history of chronic low back pain with a discogenic, spondylitic, radicular and myofascial components. The degenerative disc changes are progressing with increase in neuropathic symptoms.

PLAN (answering your questions):
1. No further diagnostic tests suggested. The patient may further strongly benefit from an evaluation by a pain specialist or neurologist to better define the physical findings and impairments.
2. Interventions:
a. The patient may benefit from a trial of lumbar epidural steroid injections. If these provide sufficient pain control not exceeding 3-4 procedures a year, surgery may be avoided or postponed.
b. An evaluation by a spine/orthopedic or neurosurgeon may be helpful if symptoms worsen. At this time the patient does not seem to be a surgical candidate, unless other treatment is not successful or not available for any reason (injections).

3. Pharmacologic:
a. The patient may benefit from using a NSAID (ibuprofen, naproxen, etodolac or other) on a regular schedule until symptoms improve and then as needed.
b. The patient may use muscle relaxants at night (Tizanidine, cyclobenzaprine, baclofen).
c. The patient may use neuropathic pain medications for his radicular pain. Choices may include: amytriptyline, nortriptyline, gabapentin, pregabalin, topiramate.
4. Rehabilitation therapy:
a. The patient would strongly benefit from a physical therapy course with core muscle strengthening.
b. He may continue his regular activities at home and work. Limitations include: no prolonged sitting, standing or bending. No strenuous activities and weight lifting more that 10-20 Lbs. (5-10 kg).
 

43 years old patient without any notable pathologies in anamnesis.
Two episodes of severe hematochezia occurred after 3-4 months from one another with total loss of 4-5 grams of hemoglobin.
The following medical tests were carried out with the motivation of hematochezia due to obscure intestinal bleeding:
-EGD (esophagogastroduodenoscopy): within normal limits.
-Colonscopy: within normal limits.

Besides those examinations, we have the medical report of which, the patient tells he underwent also digestive system X-rays with contrast medium and capsule endoscopy camera (digestive system micro camera) without any pathological evidences.
Therefore, at any next episodes, it was deemed it necessary to proceed with carrying out an arteriography with contrast medium during the bleeding episode.
 

The patient is presented for consideration of diagnostic strategies for his anemia. This 43 year old male has had two episodes of hematochezia in a 4 month period and lost 4-5 grams of hemoglobin. He has undergone EDG, colonoscopy and video endoscopy. No site of bleeding was found. He apparently also had conventional GI tract X-rays (UGI Series and Barium enema?) which were unrevealing.

I have summarized all the information I have about this patient. One crucial detail I don't know is how long after the hematochezia were the various studies performed: obviously if they were not done at the time of the bleeding the tests might well not reveal anything. Unfortunately this problem is common here in our Hematology Clinic and we don't have any novel diagnostic approaches. We carry a number of patients along in the clinic who simply submit to regular checks of their hemoglobin and ferritin and they are periodically given intravenous iron if they can't keep up their ferritin using oral iron supplements.
Diverticular disease would probably be the most common cause for hematochezia in our clinic. Internal hemorrhoids would be second (especially if the imaging was done after the bleeding stopped).

We tend to think these chronic bleeders who don't have one of the above causes for hemotchezia have a small area of angioectasia somewhere along the GI tract that could be missed by the above studies. As you probably know, angioectasia is sometimes associated with aortic stenosis; does he have a murmur? One variant of that would he hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome).

There is always the worry that they have some malignancy in the small bowel (sarcoma, lymphoma or adenocarcinoma) that cannot be appreciated by any of the above tests. Weight loss and pain might be clues and if these symptoms are present, the next step would be a CT scan with oral and iv contrast.
If the above studies were not done while he was actively bleeding, I would first repeat them when he has his next bleed. If he really has hematochezia, I'd start with the colonoscopy. There has to be blood mixed with stool that is visible, not just a guaiac-positive stool that is dark, before redoing these studies
Arteriography isn't going to be helpful unless he is bleeding briskly--your radiologists/angiographers can tell you, based on their experience, how fast the bleeding must be to see on angiogram.

Questions (In summary)-
1. Diagnostic hypotheses: diverticular disease, occult hemorrhoids, angioectasia, hereditary hemorrhagic telangiectasias.
2. Further studies would include a CT scan with oral and IV contrast
3. I would agree with arteriography as a last resort, but only if he's bleeding fast enough.
4. At least up until now at this clinic, we have been content to simply support these patients with blood and iron and not resort to exploratory laparotomies, unless a case can be made for the presence of a tumor.

21 years old female who provided us medical report of her endocrinological examination without giving us her anaemnesis.
From her medical report we deduce that the patient suffers from “Basedow’s Hyperthyroidism in autoimmune non-nodular thyroiditis (Hashimoto’s thyroiditis). Under therapy with Tapazole at the dosage of 2 tablets daily with FT3 and FT4 values within normal limits and TSH=0.00” . In the light of such values and of the clinical picture, the specialist confirmed the current therapy with Tapazole (2 tablets daily) suggesting therapeutic dosage of 131 Iodine after examination at nuclear medicine department.

On completion of the diagnostic clinical picture what highlighted during the neck ultrasound scan carried out is reported:
“Thyroid shows a slight prevalence of the right lobe and it is increased in volume as a whole. The echostructure of the whole glandular parenchyma appears moderately dishomogeneous without the nodule formations being however verifiable. The thyroid edges appear normal. The size of the right thyroid lobe being 4x2.2x1.8 cm. The size of the left thyroid lobe being 3.8x1.8x1.6 cm. Bilaterally in laterocervical area no pathological lymph nodes are appreciated.
The submandibular ones are normal. The ultrasound scan picture is compatible with diffuse hypertrophy not being able to exclude thyroiditis”.

I am asked to provide an opinion on the case of a 21 years old woman.
The history lacks in detail and is a bit contradictory. It mentions “Basedow’s hyperthyroidism and Hashimoto’s thyroiditis”. While the nomenclature varies, the two conditions can both cause hyperthyroidism but are distinct. As correctly stated in the ultrasound report, the ultrasound description is consistent with both conditions and cannot distinguish reliably. I will discuss both conditions.

Hashimoto’s thyroiditis is most often associated with hypothyroidism, but it may have a transient short phase of hyperthyroidism early on. Hyperthyroidism from Hashimoto’s thyroiditis does not require treatment other than symptom control (for example with beta-blockers) as it resolves spontaneously over a few weeks. Moreover, since hyperthyroidism in Hashimoto’s thyroiditis is caused by release of previously formed and stored thyroid hormone and not by new production of thyroid hormone, methimazole, which blocks the synthesis of thyroid hormone, will not be effective in this condition. For the same reasons, radioactive iodine would not be recommended in such a case.

Basedow’s disease (Graves’ disease in the English literature) is in contrast caused by ongoing thyroid hormone formation and therefore does not remit spontaneously, at least not in the short term. Because of its mechanism, Basedow’s hyperthyroidism can be corrected with methimazole.

The most direct way to distinguish the two forms is to perform a radioiodine uptake test, but this is not always necessary. For example, if there is evidence of hyperthyroidism lasting longer than 6-8 weeks, in a patient without thyroid nodules, then Basedow’s disease is very likely. Tests for TSH receptor antibodies also indicate Basedow’s disease when positive. Since the patient is on methimazole, I will assume that she has been correctly diagnosed with Basedow’s hyperthyroidism and I will answer her questions consequently.

1) Do you agree with the therapy set out and the suggested one?
There are 3 therapeutic options in Basedow’s disease. Methimazole is an effective way to control hyperthyroidism, while hoping for a remission. Most typically, patients are maintained on the medication for 12-18 months after which the drug is slowly tapered until it can be stopped or until there is evidence of returning hyperthyroidism. A good number of patients (maybe 40%) achieve a durable or permanent remission. Many more though will have to decide whether to resume methimazole or turn to one of the other two options, because of relapsing hyperthyroidism. Methimazole is safe, but it can cause agranulocytosis in up to 1/300 cases. While the phenomenon is reversible with discontinuation of the pill, patients must be instructed on promptly reporting high fever and any symptoms of infection, a sign of possible agranulocytosis. Fatalities are extremely rare, but have been described. In this case, I do not think that the low TSH is necessarily an indication of failure of methimazole and should result in an absolute recommendation for an alternative treatment. Titration of methimazole with verification of compliance is expected to result in control of hyperthyroidism in almost all cases.
The second option is radioiodine, which I will discuss below. The third is surgery: total thyroidectomy. Surgery is effective in treating Graves’ disease, but it is invasive, expensive and requires some 7 to 20 days of recuperation. Specific risks from thyroid surgery include permanent hoarseness (from damage to the recurrent laryngeal nerve with vocal cord paralysis) and hypocalcemia from hypoparathyroidism. These outcomes are rare (<1%) in the hands of experienced surgeons.

2) With regard to this, which could be the side effects of Radioiodine therapy, in particular with regard to fertility?
Radioiodine is effective in treating hyperthyroidism, relatively inexpensive and is done on outpatient basis. It basically achieves the same goal of surgery, without anesthesia, without neck scar and without risks to the vocal cords. Radioiodine is absolutely contraindicated during pregnancy and lactation. One single dose is usually sufficient but occasionally a second treatment becomes necessary. Several studies have shown no significant fertility risks with radioiodine treatment; however we recommend avoidance of pregnancy for six months after the treatment. Some people who have the eye manifestations of Graves’ disease (proptosis, diplopia, eyelid swelling) may have a worsening of their ocular symptoms after radioiodine. For those patients, a brief period of treatment with corticosteroid is often given after the radioiodine treatment. Whether radioiodine can cause the new onset of this condition in patients who don’t have it remains unclear. Some studies suggest so, but this is not the experience of many clinicians using radioiodine regularly, like me. Both radioactive iodine and surgery will result in permanent hypothyroidism, easily corrected with thyroid hormone, a treatment without side effects if well monitored.

3) Any alternative and/or complementary therapies?
I do not know of any other alternative proven to be equally safe and effective. Some studies suggest a benefit of selenium supplements in thyroid autoimmunity, but these studies await confirmation.

4) Do you suggest to carry out further diagnostic medical tests?
From the reports received, it is not clear whether the diagnosis of Basedow’s was based on radioiodine uptake, TSH receptor antibody tests, or duration of hyperthyroidism. If any of those was done and found to be consistent with Basedow’s then, I do not recommend any further tests, other than periodic thyroid function tests, liver function tests, complete blood counts.

5) Prognosis?
Prognosis is excellent, with most patients going on with a normal life expectancy and quality, independently of the treatment modality chosen.

40 years old female that became symptomatic 10 years ago with relapsing fever episodes, persisting asthenia and appearance of vitiligo on the hands.
Therefore, in those days, routine blood tests were carried out with the only finding of a TSH increase (approximately 7.00 mclU/mL) in FT3 presence and FT4 within normal limits, subsequently a diagnosis of hypothyroidism was placed with indication to follow a substitution treatment with Eutirox 50 mcg at a dosage of 1 tablet daily with normalization of thyroid hormone levels.
After a few months, Eutirox was suspended, upon her doctor’s advice, and the patient didn’t follow any treatments for about 10 years without carrying out any thyroid function blood tests and reporting a satisfactory health condition for the whole period.

Moreover, it is observed that in the aforesaid period the patient however carried to term 3 pregnancies.
An year ago appearance of relapsing headaches for which the primary care physician, based on the thyreopathy anamnesis, advised to carry out:
- Thyroid ultrasound scan that was interpeted: “Thyroid within normal limits as for size, showing inflammatory dishomogeneous echostructure without any focal nodular alterations in context. No laterocervical adenomegalies. Trachea in axis.”
- Blood tests were carried out with finding of :
Antimicrosomal antibodies (TPO) 176.10 Ul/ml (0 – 34)
Antitireoglobulin antibodies 414.80 Ul/ml (0 – 115)
Thyroid-stimulating hormone (TSH) 5.670 mclU/ml (0.270 – 4.200)
Free Thyroxine (FT4) 1.09 ng/dL (.93 – 1.70)

As a result of the examinations performed, the endocrinologist placed a diagnosis of hypothyroidism in probable Hashimoto’s thyroiditis advising a substitution treatment with Eutirox (dosage of 100 mcg daily) during which, however, the following side effects appeared:
-Feeling of eyes “swelling” that the patient reports nearly as a sensation of the eye outside the orbit and tendency to double vision that nearly provokes faint . A facial MRN was carried out without contrast medium ,and further facial skeleton MRN with contrast medium was performed with both medical reports of normality, in particular no alterations involving the sellar cavity, the hypophysis and the optic chiasm.
-Tachycardia.
-Outbursts of anger;
-Sleepiness;
-Disturbed sleep;
-Headaches, always in precycle phase, that have gradually become more intense and extended in time while, before, they were often present but without ever being linked to the menstrual cycle.

On completion of the clinical picture, frequent tachycardia and sudden change in pressure are observed following with Holter test without any pathology finding.
As a result of such side effects, the patient suspended the therapy again and carried out follow-up hematochemical examinations with the following results:
TSH 8.670 mclU/mL (0.270 – 4.200)
FT4 1.08 ng/dL (0.93 – 1.70)
FT3 3.47 pg/mL (2.00 – 4.40)
Taking into consideration the high TSH level, the patient decided to resume, in complete independence, following consultation with the family doctor, therapy with Eutirox at the dosage of 75 mcg daily (underdosed compared to the 100 mcg advised, at first, by the endocrinologist that, as already explained, was badly tolerated from the patient). 

The patient's clinical history is consistent with Chronic Lymphocytic Thyroiditis or Hashimoto’s thyroiditis (those are synonyms), with “subclinical” hypothyroidism. This is a common condition caused by the immune system mistaking the thyroid gland for a foreign body and therefore attacking it. While this sounds ominous, the only significant result is thyroid dysfunction which can be mild, as in this case, or profound. In this case, a legitimate attempt at replacing thyroid function with thyroid hormone in pills has resulted in multiple symptoms, some of which are suggestive of excessive thyroid hormone levels. However, the question of whether actual overdose has occurred cannot be answered with the data at hand, as a TSH level taken during the treatment with Eutirox 100 has not been provided. In any case I will answer the well formulated questions as precisely as possible.

1) What is the diagnosis on the basis of the examinations carried out? If it’s not possible to place a sure diagnosis, what diagnosis do you think is more probable?
Both the ultrasound description and the antibody tests and the thyroid dysfunction clearly indicate that the diagnosis is Hashimoto’s thyroiditis as detailed above.

2) Further necessary medical tests are advised? In the event of affirmative answer, which medical tests do you advise and why?
The diagnosis is well established and I do not think additional tests are necessary, especially if the symptoms observed during the treatment with Eutirox 100 have now resolved.

3) What therapy do you suggest? In particular, does a substitute for Eutirox exist in order to avoid aforesaid side effects when reaching the daily dosage of 100 mcg or higher? Speaking of this, which is your opinion on Novothyral and the possibility to use it in this patient's case?
In most cases of subclinical hypothyroidism, treatment with levothyroxine (for example Eutirox) alone is sufficient. Thyroid hormone therapy is a very benign treatment, in which the administered chemical compound is simply a “replacement” for a chemical that is natural to the body, not really a drug. Of course excessive doses can result in symptoms of hyperthyroidism, but most people tolerate the medication exceptionally well.
In this case, given the mildness of the hypothyroidism, a dose of 50 mcg daily should be sufficient to correct the abnormality, without causing overdose. However, should the patient not tolerate thyroxine at all (which would be unlikely), one could consider no treatment. Several studies have addressed the long term effect of subclinical hypothyroidism, when it is not treated. Some of these studies have suggested that some parameters of cardiovascular health such as lipid levels and signs of endothelial dysfunction may be altered in subclinical hypothyroidism. However results have been inconsistent. Moreover, there is no study suggesting increased cardiovascular mortality or increased risk for cardiovascular event (such as myocardial infarction and strokes). As a consequence, treatment of subclinical hypothyroidism is not considered mandatory. Novothyral contains the same active compound as Eutirox (thyroxine also known as T4) plus a more potent form of thyroid hormone (tri-iodothyronine aka T3). Since the patient had side effects from T4, the addition of T3 would only be expected to make her symptoms worse, so I do not recommend it.

4) The possible therapy with Eutirox or other drug is to be followed all life long? Speaking of this, do you think that the suspension of Levothyroxine 10 years ago can be responsible for the current worsening of the hypothyroidism clinical picture?
Hypothyroidism from Hashimoto’s thyroiditis tends to be irreversible, so, if it is decided that treatment is to be given, then yes, it is for life. I do not believe that stopping the medication 10 yrs ago had any influence on the current status of the patient.

5) Prognosis?
The prognosis of hypothyroidism is excellent as appropriate replacement with thyroid hormone is expected to result in normal life, both in terms of duration and quality. Similar prediction can be made if treatment is not selected and the thyroid dysfunction remains mild. However, in many cases of Hashimoto’s thyroiditis, subclinical (mild) hypothyroidism will progress with time to a more severe form of thyroid hormone deficiency (overt hypothyroidism), which will require treatment. This process is thought to be independent of whether thyroid hormone replacement is started early or not, but of course if the patient is already on thyroid hormone at the time when the thyroid becomes completely atrophied, then there will be no clinical consequences.
In terms of my recommendations for this patient, this is what I suggest:
a) Start treatment with Eutirox 50. If this is well tolerated and the TSH returns to normal, then the goals are achieved.
b) If Eutirox 50 is not tolerated, then one can consider half tablet per day (25 mcg), or no treatment, with the idea that if hypothyroidism becomes more severe, then the same steps will have to be tried again.
c) If Eutirox 50 is well tolerated, but TSH does not return to normal, then a dose of 75 mcg (one and one half 50 mcg tabletor one 75 mcg tablet, I do not know whether Eutirox comes in the 75 mcg strength) can be tried.

15 years old male in good health conditions. 5 months ago he showed ingravescent asthenia, fever and diarrhea, therefore he performed hemochrome with finding of severe anemia and thrombocytopenia, LDH increase, bilirubin increase and presence of schistocytes. The patient was hospitalized and he was first treated with intravenous steroids and IgG without any improvements of the clinical picture; after diagnostic re-evaluation, that allowed to place diagnosis of “Thrombotic thrombocytopenic purpura”, a therapy with plasmapheresis with blood count normalization after 15 courses was started.

At admission:
Direct Coombs test positive (4+) for C3d. Indirect coombs positive (1+).
Reported:
- Normal kidney function (creatinine 0.9 mg/dl)
- Moderate microscopic hematuria
- Absence of proteinuria

1 month later:
- Direct Coombs test positive (3+) for C3d (3+)
- Lupus Anticoagulant: negative.
A dosage of ADAMTS-13 towards the end of plasmapheresis courses resulted at the lower limits without any findings of anti ADAMTS-13 antibodies, that was considered a non-relevant sign in view of the current therapy.
He was discharged with cortisone therapy by oral way that was reduced in approximately three weeks. Persistence, in the post-hospitalization, of hematuria and proteinuria and positive ANA 1:640, with direct Coombs test positive for C3 and uncertain anti-native DNA antibodies (IFA test).

1.5 months later:
- Direct Coombs test: Positive (4+) for C3d (4+)
- Indirect Coombs test: Positive (2+)
Specificity: Anti-Jka
Titre: 1:1
- ANA: Present 1:640 (speckled) (meaningful values>1:160)

2 months later:
Anti-native DNA antibodies (IFA method): Uncertain (meaningful values >1:10)
Anti-native DNA antibodies (immunoenzymatic test) 73 U/ml (meaningful values > 100 U/ml).

Anemia and thrombocytopenia reappearance two weeks after suspending the steroid therapy, therefore the patient was hospitalized again 2 months after the initial episode. During that hospitalization, he started again steroid treatment and plasma therapy (1000 ml) for 4 days; the administration of anti-CD20 monoclonal antibody (Rituximab) started and 4 infusions were carried out at a standard dosage. Transfusion with 2 leukodepleted red cell concentrate was carried out.
Progressive and fast remission of the clinical picture with hemochrome and LDH normalization.

Patient moved to the nephrology ward to carry out a kidney biopsy after injection of local anaesthetic for diagnostic definition of glomerulonephritis with the following result: Histological picture of glomerulonephritis with focal and segmental capillary necrosis with IgA deposits.
From the microscopic point of view the biopsy highlights, among other things: “… immunofluorescence survey carried out with fluorescinated anti-immunoglobulin antibodies, complement fractions, light and heavy chains, has evidenced granular deposits of IgA+ and C3++ and IgM+ at mesangium level and on loops."

A new ADAMTS-13 dosage taken at the beginning of the relapse was carried out with the following results:
Functional ADAMTS13 activity (FRET) <3% (normal values ->45-138%)
Anti-ADAMTS13 antibody present (normal values ->absent)
ADAMTS13 Antigen (ELISA) 9% (normal values ->40-155%).
Direct Coombs test: positive (4+) for C3d (3+)
Anti-DNA antibodies: absent
ANA: present 1:320 (speeckled) (meaningful values: >1:160)
ENA: absent
Lupus Anticoagulant: positive
Anticardiolipin antibodies (phospholipids): slightly positive
IgM 4 MPL/ml (vn <12)
IgG 17 GPL/ml (vn <12)
IgG-IgA-IgM: within normal limits
C3: 0.70 g/L (vn: 0.90-1.80)
C4: 0.06 g/L (vn: 0.10-0.40)

1 month later:
Creatinine 0.8 mg/dl.
Hematocrit 38.4%.
Hb 12.6 g/dl .
WBCs 5,500/mcl.
Platelets 169,000/mcl.
Urine test: microscopic hematuria (1770 GR/uL) – proteinuria 50 mg/dl
C3: 0.64 g/L
C4: 0.01 g/L

1.5 month later:
Creatinine 0.9 mg/dl.
Ht 40.6 – Hb 12.9 – WBCs 12,000 – Platelets 275,000
Schistocytes: 21/a thousand
LAD 308 U/L (vn 200-450)
Urine test: microscopic hematuria (2,464 GR/uL) – proteinuria 100 mg/dl
ANA: present 1:320 (speckled)
ENA: absent
C3: 0.76 g/L (vn: 0.9-1.8) (blood sample dated 10/03/2011)
C4: 0.10 g/L (vn: 0.1-0.4) ( “ “ “ )

We have reviewed the history provided and the laboratory data on this patient. The history is nicely outlined in the referring documentation. This patient presented with clinical syndrome of fever, fatigue, and diarrhea. Laboratory findings showed severe anemia with findings of microangiopathic hemolysis (schistocytes, hyperbilirubinemia, elevated LDH) and severe thrombocytopenia. He was later documented to have fluctuating ADAMTS13 activity that appeared to correlate with the hematologic abnormalities. He also had urinary findings of hematuria, moderate proteinuria, and creatinine as high as 1.4 mg/dL. Further lab evaluation included low complement levels, positive ANA of a high titer at 1:640 with negative double stranded DNA antibodies.

The patient was initially treated with steroids and intravenous immune globulin (IVIG) without improvement in his hematologic findings, which came only after the addition of plasma exchange. After later tapering his steroids, his hematologic parameters worsened with return of anemia and thrombocytopenia. At that time his creatinine was elevated to 1.4 as noted. He was treated again with steroids and plasma therapy. Rituximab was added with eventual remission.

A renal biopsy was obtained after treatment outlined above, which revealed glomerulonephritis with focal and segmental capillary necrosis on light microscopy. By immunofluorescence, granular deposits of IgA+, C3++, and IgM+ were seen in the mesangium level and capillary loops. (Of note, neither the original biopsy report nor the slides themselves were available for review). His creatinine later improved down to 0.9 mg/dL.
Based on the findings above, the patient likely has a unifying diagnosis of Systemic Lupus Erythematosus, supported by low complement, positive ANA, cytopenias, and renal abnormalities (hematuria, proteinuria, renal dysfunction). His cytopenias are also suggestive of Thrombotic Thrombocytopenia Purpura (TTP), also supported by the low ADAMTS13 activity in the presence of inhibitors. He has other auto-antibodies as well, including positive direct Coombs test for complement, and a positive lupus anticoagulant, the clinical significance of which are not clear but which support a diagnosis of underlying systemic autoimmune disease.

Regarding the specific questions posed:
1. The first and the second episode of TTP can be considered “secondary” to a systemic disease or the (likely) systemic disease is coexistent with the TTP?
We believe the TTP to be secondary to Lupus. The association of TTP with Lupus has been well described.

2. The antibody for ADAMTS13 was negative after 12 sessions of PEX (in total 15 were carried out), while it was positive after 3 dosages of Rituximab (in total 4 doses were administered). If a further TTP relapse would occur, do you deem it advisable to carry out (at least at first) the PEX or the administration of other doses of Rituximab? Vincristine is to be used?
The initial treatment for TTP acutely or in the setting of recurrence needs to focus on plasma exchange to remove the offending antibodies and replace deficient ADAMTS13 protein. Immunotherapy such as rituximab, cyclophosphamide, and corticosteroids generally do not work quickly enough to reverse the immediate, life-threatening hematologic and renal abnormalities associated with TTP. With respect to possibly repeating a course of rituximab, our practice is to follow the number and percentage of B-cells in the peripheral circulation by flow cytometry, which remain depleted for 6-9 months on average. This effect can last even longer if additional immunosuppression is used. We also monitor quantitative IgG levels monthly for several months after rituximab and consider repletion if levels are very low (under 400) to reduce the risk of serious infection. If the patient relapsed, there would be no rationale for a repeat course of rituximab if B cell levels remain very low or undetectable. We do not see a role for vincristine.

3. Do you think splenectomy could have a clinically positive role?
Splenectomy would only be considered if the patient remains refractory to all other forms of therapy, which would include repeated courses of Rituximab as outlined above.

4. After the first episode of TTP steroid was reduced until suspension (it was suspended in approximately 2 weeks before the 1st relaps). How is it advisable to reduce steroid now (after the 1st relapse)? Is it advisable to suspend it or do you suggest to keep a maintenance dose? (From the first 50 mg/a day, taken for about 1 and a half month, at present - he takes 25 mg/a day).
We would suggest tapering the steroids slowly over the coming months with ongoing monitoring of CBC, reticulocyte count, and LDH to evaluate for relapse. The presence of glomerulonephritis should also be considered, as the labs provided showed moderate proteinuria and hematuria. Complement levels should also be followed as another marker of Lupus activity to address further tapering of steroids. If tapering is unsuccessful, the addition of maintenance immunosuppression with mycophenolate could be considered to address the various manifestations of his Lupus.

5. Is it advisable to schedule the administration of Rituximab “pre-emptive?” If the answer is yes, based on which parameters?
We would not use Rituximab pre-emptively. Recurrence of TTP at this point is uncommon. As outlined above, we would suggest following B-cells via flow cytometry and only use additional Rituximab if there is recurrence and his B-cells have recovered.

6. How can the steady positive result of the direct Coombs test can be interpreted only for C3d?
We do not know the clinical significance of the positive Coombs test or whether this was contributing significantly to the hemolysis that he had. This may be just another autoantibody that the patient has in the setting of underlying autoimmune disease, and certainly red blood cell antibodies and autoimmune hemolytic anemia can be seen in the context of SLE. If the patient has a normal reticulocyte count, normal LDH and haptoglobin in the face of persistently positive Coombs test this supports this not being of clinical relevance at present. We have followed patients with chronically positive Coombs test who do not have clinical autoimmune hemolytic anemia and no treatment is warranted in this scenario. Coombs test can also be positive after red blood cell and plasma transfusions and this may be a contributing factor.

7. How can C3 and C4 depression be interpreted especially in the active moments of the disease?
The hypocomplemetemia is consistent with Lupus, and is often low in the setting of Lupus flares.

8. The suspect of an autoimmune disease is clear, mainly from the examinations carried at the time of the 1st relapse. Which autoimmune disease do you think we are dealing with? Is it possible to talk of LES or Lupus-like? Is it possible the presence of a congenital anomaly of the “complement?” (Anti-DNA antibodies are always negative).
As outlined above, we believe the patient has Systemic Lupus Erythematosus. The recovery of complement levels to normal after treatment speaks against a congenital complement deficiency.

9. How can the kidney biopsy be interpreted and in particular the immunofluorescence picture? Could it be possible this picture was modified from the intake of Rituximab + steroid when carrying out the biopsy?
The biopsy report describes glomerulonephritis with immunofluorescence positive for IgA, IgM, and C3. The classic pattern of Lupus Nephritis is the so-called “full house” pattern, which also includes positive staining for IgG and C1q. However, the patient had received various forms of immunosuppression prior to the biopsy, which may have modified the original histology. If electron microscopy was performed, the presence of tubuloreticular inclusions are also highly suggestive of Lupus Nephritis.

10. The therapy the young man (15 years) carried out will have negative effects on his growth? Do you deem it necessary to monitor any particular lab or clinical parameters?
Long term steroid use can certainly impact linear height but we would not expect the amount of steroids that he has had to date to have significant long-term sequelae. It is important to taper his steroids, however, as suggested, as chronic use (more than 6 months) of relatively high doses could adversely impact his growth and lead to other late effects such as osteonecrosis, risk of cataracts, osteopenia, etc. Monitoring his height and weight at this point should be sufficient and attempting to actively taper his steroids with a plan of introducing alternative immunosuppression (such as mycophenolate) if this is not possible.

11. The young man has a twin sister who is currently in good conditions (the main lab examinations are within normal limits). Is it advisable for her to undergo particular haematological or genetic surveys?
No specific studies are indicated for his twin sister who is presumably asymptomatic. We do not believe there is likely to be a significant inherited nature to this illness apart from the relatively minor increase in the incidence of systemic autoimmune disease that is seen in immediate family members.

31 years old male without any significant notable pathology in anamnesis.
A month ago, during a soccer match, the patient had a trauma at the right shoulder level, therefore, he immediately went to the Emergency Room , where the medical staff placed a diagnosis of “Right glenohumeral luxation.”
The Emergency Room orthopedist reduced luxation, after local anesthesia, asking the patient to return the following day for a follow-up examination. The day after a conservative treatment was prescribed to the patient who had to wear a brace (Gibaud Ortho) for 5 week.
During the first days of the event, the patient treated pain, of modest importance and bearable, taking Tachipirina 1000 twice a day. At present, the day pain has completely disappeared reappearing a bit at night and affecting mainly the forearm.

3 weeks later the patient decided to carry out a right shoulder MRN, with the following medical report:
“A depression of the anatomical profile of the posterolateral region of the humeral head is appreciable with signs of subcortical medullary edema, as for Hill-Sachs lesion. Concomitant alteration of signal with characteristics of hyper-intensity of the anterior inferior glenoid lip, as for Bankart lesion: at the basal assessment, however, it is not possible to stage the fibrocartilage lesion nor define the associated capsular ligament lesions, therefore an integration through arthro-MR examination is advised.
The supraspinatus and infraspinatus muscle tendons don’t show solutions of continuity or avulsion symptoms; the tendon tissue structure is homogenous.
No effusion of the deltoid subacromial bursa. Normal muscle trophism of the supraspinate and the deltoid. Findings within normal limits for the subscapularis muscle tendon.
The long head tendon of the brachial biceps muscle starts in the reflection pulley; the insertion of the biceps anchor is intact.
Presence of intraarticular effusion of moderate importance with distension of axillary and subscapularis-subcoracoid recess in presence of hypointense nucleus placed in the most declivous area.”
 

Below are answers to the questions:
1) The conservative treatment carried out till today is correct?
Yes. The shoulder had closed reduction of a traumatic glenohumeral dislocation, anterior, with postoperative sling immobilization for five weeks.

2) Do you deem it necessary to wear the brace for 4 or 5 weeks? If the brace is worn for 5 weeks, does the patient run the risk of suffering from too much shoulder rigidity?
There are differences of opinion regarding the need to immobilize the shoulder after dislocation. It is standard practice to immobilize for 4-6 weeks, but there is not much difference in re-dislocation rate if the shoulder is or is not immobilized. The risk of loss of motion is very small, though.

3) In order to avoid the luxation from becoming relapsing, do you deem it necessary or useful to carry out a surgical operation or, based on the clinical picture described, the rehabilitation therapy is to be considered sufficient?
The chance of recurrent dislocation is in the range of 40%, regardless of therapy or not. I would not recommend surgery now, though, because the risk of not having another dislocation, on the other hand, is in the range of 60%. The level of activity (such as sports) is one of the important factors that will affect the re-dislocation rate.

4) Do you think that lesions highlighted from the MRN could, with the passing of time, gain a complete recovery?
The Bankart and Hill-Sachs lesions demonstrated on the MRI are typical findings after traumatic shoulder dislocation. They typically do not heal spontaneously. The Bankart lesion could be repaired surgically, but this should be done only if the shoulder has recurrent instability (dislocations). The shoulder function can return completely to normal and have no further problem, though, even if the lesions do not heal.

5) If a rehabilitation therapy is necessary, which kind do you suggest?
Pendulum exercise, elastic band (Theraband), resistance exercises to regain strength. However, no matter how strong the shoulder is, the shoulder can accidentally re-dislocate (when the patient did not expect a force and when the muscles were not contracted). Avoid overhead weight lifting with the weights behind the head (in other words, be careful of excessive extension of the shoulder in the overhead abducted externally rotated position).

6) If a surgical operation is needed which are the centers of excellence in Italy?
Where in Italy? Dr. Alex Castagna in Milan trained in USA with Dr. Steven Snyder. He is good, but there are others.
 

Patient aged 89 with no anamnestic and clinical information available. Following a recent appearance of symptomatology linked to a suspect of light stroke, two appropriate diagnostic medical tests were carried out: Echo Colour Doppler Test of the supra-aortic trunks and brain CT scan.

Following, the relevant medical reports are related:
1) Echo Colour Doppler Test of the supra-aortic trunks:
   “Diffuse sclerosis of vessels examined. On the right, fibrous plaque which involves the whole bulb and the origin of the internal carotid artery resulting in a stenosis of 70-75% with acceleration in the flow speed of 140 cm./sec. On the left, fibrocalcific plaque with irregular edges and dishomogeneous structure, with stenosis of 60% of the origin of the internal carotid artery without any flow accelerations. Right vertebral artery within normal limits. Left vertebral artery with flow clearly demodulated and reduced.The picture would place indication for a surgical operation of thromboendarterectomy (TEA) of the right carotid bifurcation, for the importance and the bilaterality of the lesions besides the specific symptomatology. However, taking into consideration the patient’s age, an anesthesiology assessment is advised before taking any decisions.
Keep following the antiaggregant treatment (Ticlopidine). To add, Prisma tablets 50 mg., 1 tablet twice a day for 3 months and then 1 tablet a day for another 6 months.”

2) Brain CT scan:
   “Examination carried out without contrast medium, with axial sections at the apex base. The posterior cranial fossa is normal.
At supratentorial level, small ischemia foci seemingly of recent origin in the white matter of the radiate crown from the right side.
Moderate enlargement on atrophic base of the ventricular system and of sulci. Slight diffuse hypodensity of the lateral and supraventricular white matter of both hemispheres, of non-specific appearance and expression of regressive changes on chronic ischemic vasculopatic basis with regard to age or to possible vascular risk factors.”

This 89 year old woman had undergone brain CT and Carotid duplex examination because of a suspected minor stroke, yet history and clinical findings were not provided.

Brain CT revealed chronic ischemic changes and ischemic foci suspected to be of recent origin in the right corona radiata. Carotid duplex revealed findings of bilateral carotid atherosclerosis, without any flow acceleration on the right ICA and up to 140 cm/sec on the left ICA. Right Carotid Endarterectomy was suggested.

Diagnostic and therapeutic advice:
I strongly recommend first careful history and Neurological assessment to determine if there was a recent ischemic event that is clearly in the distribution of right ICA. If this is the case, I would assess the degree of carotid stenosis by another imaging modality such as CT or MR angiography.
I would recommend right CEA only if all the following are met:
1. A recent clinical ischemic event that is clearly in the distribution of the right ICA.
2. Conformation that stenosis in the right ICA is indeed severe, preferably by CT or MR angiography.
3. No contraindications to surgery.

Suggest in any case continuing antiplatelet therapy, intensive statins to a LDL cholesterol goal of up-to 70 mg/dl and best control of any other medical and lifestyle risk factors.
For carotid stenosis that is asymptomatic or symptomatic in any other vascular distribution, no CEA or carotid artery stenting is recommended given the patient's age. In this case best medical management is the best option.
In case of clearly high grade symptomatic carotid stenosis and high surgical risk, an alternative option could be carotid artery stenting. However, octogenerians carry a particularly high procedural risk from carotid artery stenting, so given the patient's age this option is not desirable.