Encephalopathy in Hepatocellular Carcinoma

Portosystemic Encephalopathy in Hepatocellular Carcinoma
Short Summary

Adult male with a history of hepatitis C, non-Hodgkin’s lymphoma (NHL) and hepatocellular carcinoma. Patient treated for NHL with CHOP-R 4 years ago. However, post-treatment, he had continued presumed bone marrow suppression. He was diagnosed 2 years later with HCC and underwent TACE with good effect. Since the TACE, the patient has had persistent and worsening hepatic dysfunction with portal hypertension and ascites. Recently, the patient developed encephalopathy and was treated, as described below, with fast return to consciousness.

Patient's Questions

1) Any support therapy to suggest?
2) Is there a solving therapy? In particular, do you think that a liver transplant is possible? Is it possible to use the stem cells?

Medical Background

History:
• 1979: Discectomy L5-S1;
• 2003: Hypercholesterolemia and diabetes mellitus.
• 2004: Unappreciated inferior AMI; following PTCA + stent on CX;
• September, 2005: Finding of HCV Ab positive, non confirmed at the following tests; HBsAg negative, HBsAb positive, HBeAb positive.

• September, 2006: Epigastric mass biopsy (bulky) with histological examination: Non-Hodgkin B-cell lymphoma diffuse big cells. Bulky stage IIIA (weight loss 20 kg connected to the region of the disease).
• September, 2006: 1st CHOP course, at standard dosages.
• From the second course R-CHOP with vinblastine and dosages at 75%. He undergoes 4 total courses.
• At “intermediate” re-evaluation, complete remission PET scan and a persisting residual mass at CT scan.

• Since then severe neutropenia and appearance of suspected testicular tumefaction not confirmed from the ultrasound scan (varicocele).
• January, 2007: Bone marrow biopsy-normal poiesis,reactive lymphoid infiltrate. Bone marrow aspiration: slight dysplasia, but not conclusive for myelodysplasia.
• January-February, 2007: Persisting neutropenia with 600 neutrophils and moderate thrombopenia 96,000. Prescribed Myelostim every other day. Abdominal CT scan: Residual.
Radiation therapy 30.6 Gy on the residual abdominal mass, ended on 4.17.07.
• October, 2007: WBCs 1800, N 600, Mo 300, Hb 13, Platelets 74000, Alanine Aminotransferase 41,
   gGT 235. Chest CT scan: inv/neg; abdomen: In hepatic area, in correspondence of the V and the VI hepatic segment the presence of some nodule formations, deserving close examination, is noticed (negative abdominal ultrasound scan is signalled the previous month); spleen 14.5 cm (at ultrasound scan).
• November, 2007: Alpha-fetoprotein 8, abdomen MRN: Diffuse hepatic micronodules of probable degenerative nature.
   Centimetric area of premature enhancement at S5 level, possible expression of pathology localization.
• June, 2008: Appearance of a new hepatic lesion confirmed by CT scan and ultrasound scan.
• July, 2008 Esophago-gastro-duodenoscopy: Esophageal varices FI blue, without any red signs.
• August, 2008 Hospitalization in hepatology ward carrying out hepatic biopsy of nodules with diagnosis of nodules of regeneration in cirrhosis.
   Alpha-fetoprotein 5.
• November, 2008: hepatilogic vision after CT scan that highlights progression of hepatic and abdominal nodules. Alpha-fetoprotein 6.

• December, 2008 the patient was hospitalized. 
   Biopsy of hepatic lesion: Trabecular HCC in hepatic nodules. Echocardiography: normal.
• January, 2009: The patient underwent a TACE (Hepatic artery chemoembolization).
• 03/05/2009 Abdomen CAT scan with contrast medium: Excellent response to treatment. However small spots, due to disease residue, still persist.
   Alpha-fetoprotein 5.
• March, 2009: Hospitalization due to ascitic decompensation. A paracentesis was performed with removal of 4000 cc of ascitic lactescent fluid.
   Sodiuria 236 mmol/24 hours. Cytology on ascitic fluid: Negative the malignant cells research. Abdominal ultrasound scan: No portal vein thrombosis.
• April, 2009: Hospitalization due to ascites.
• December, 2010: Hospitalization due to refractory ascites.
• From January to March 2010 cyclic DH to undergo paracentesis.
• March, 2010: Hospitalization due to refractory ascites. The patient underwent 5 sessions of evacuative paracentesis.
• May, 2010 Paracentesis.

Last hospitalization due to portosystemic encephalopathy in multifocal HCC on nodular chronic hepatopathy. Examination at admission highlighted space-time confusion. At chest vesicular murmur preserved on all the lung fields, no pathological sounds added; at Heart valid heartbeats, rhythmical, 2/6 systolic murmur in the mesocardium. Moderate ascitic effusion, treatable, neither painful nor tender at superficial and deep palpation, scrotal edema; no edemas at the lower limbs.
During hospitalization the patient was treated with lactulose, enemas and ramified amino acids by injection with fast return to consciousness.

Current therapy:
Lactulose syrup, 2 spoons twice a day
Insulin glulisine (ex. Apidra), 7 UI + 8 UI + 9 UI before meals
Potassium canrenoate 100 mg (ex. Luvion), 2 tablets at 8:00 a.m., 1 tablet at 12:00 p.m.
Furosemide 25 mg (ex. Lasix), 2 tablets at 8:00 a.m., 1 tablet at 12:00 p.m.
Omeprazole 20 mg (ex. Antra), 1 tablet in the morning before meals, 1 tablet at 8:00 p.m.
Folina 1 tablet at 12 p.m.
Rifaximin 200 mg (ex. Normix), 2 tablets 3 times a day for one week then cycles of one week a month.
Hyposodic diet poor of animal proteins.
Enema with lactulose when needed.

Expert's Opinion

This consultation is based on the 3 pages summary report provided. No pathology or radiology imaging reports or films were provided. Pathology was not reviewed at our center. In reading this report, please confirm history in above paragraph is accurate assessment.

The case presentation describes an adult male with a history of hepatitis C, non-Hodgkin’s lymphoma (NHL) and hepatocellular carcinoma. Patient treated for NHL 4 years ago with CHOP-R. From the records, it appears the patient remains in remission. However, post-treatment, he had continued presumed bone marrow suppression (though now patient also has splenomegaly impacting blood counts). He was diagnosed in December 2008 with HCC and underwent TACE with good effect. AFP has never been elevated. Since the TACE, the patient has had persistent and worsening hepatic dysfunction with portal hypertension and ascites. I believe CT scan in May 2010 showed multifocal HCC.

Hepatocellular carcinoma is a fairly common disease worldwide. Unfortunately, treatment options often have limited efficacy. It is one of the few cancers that liver transplantation is considered an option. Criteria used for transplantation include patients who have a single lesion 5 cm, up to three separate lesions, none of which is larger than 3 cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases. These criteria are based on prognostic factors on which patients appear to benefit. Ultimately, a decision regarding this patient’s eligibility for transplantation requires a transplantation surgeon reviewing the films – with all images available. Based on the summary, I would be concerned that the patient is not eligible for transplantation if the disease is multifocal throughout liver. Further, it is not clear from the summary is the patient remains neutropenic and thrombocytopenic – if he does, I would assume a bone marrow evaluation would be necessary to determine extent to which bone marrow is cause of bone marrow suppression versus splenomegaly.

Other local therapies for treatment if the patient is not eligible for transplantation include chemoembolizations, radiofrequency, cryoablation or alcohol ablation. Many clinical trials have examined chemoembolization for hepatocellular carcinoma – three studies did not demonstrate a survival benefit while two others did. A meta-analysis does suggest a survival benefit (Llovet and Bruix Hepatology 2003) but patient selection is likely the most important factor. Other ablations are less rigorously studied, but have risks in patients with decompensated livers. However, in this patient, I would be very worried regarding localized therapy that will have collateral damage to non-cancerous hepatocytes. His decompensated liver makes these options contraindicated.

Chemotherapy has very limited efficacy for these patients. Sorafenib has modest benefit compared to best supportive care. It is not possible from the summary provided to determine the patients Childs Pugh score or CLIP score. Sorafenib is primary indicated in Childs A and some B patients. However, I would again be concerned regarding his blood counts since it can decrease the white blood cell count.

In my opinion, based on the limited history provided, I would favor concentrating on treatment of his hepatic dysfunction as you are doing. I am not a hepatologist – further advice regarding other strategies for his hepatic dysfunction could be reviewed with a hepatologist.
Regarding specific questions in consult:

Median survival with metastatic hepatocellular carcinoma is 9-10 months – ½ patients live longer and ½ shorter than that time. The patient’s hepatic dysfunction makes prognosis more guarded.

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