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When is it too late to treat a patient with cirrhosis?

for Health Care Providers

2: When is it too late to treat a patient with cirrhosis?

Background

The patient is a 54-year-old white man with chronic hepatitis C virus (HCV) genotype 1. He has a viral load of 128,400 IU/mL, normal alanine aminotransferase (ALT) with elevation of aspartate aminotransferase (AST) 2 times the upper limit of normal, and does not use alcohol. He had not been considered a treatment candidate for a couple of years secondary to depression and anxiety. He was managed by his primary care physician. He has been doing well recently and was OK'd by a psychiatrist for consideration for treatment. The patient returned to clinic, where additional laboratory tests reflected a worsening liver disease, although he would not agree to undergo liver biopsy. Instead, testing with HCV Fibrosure was performed, yielding a fibrotic score of 0.97 (F4 cirrhosis) and necroinflammatory score of 0.67 (A3 severe inflammation). A physical examination indicated the presence of ascites, which was confirmed by ultrasound.

Other laboratory tests and the results were as follows:

  • White blood cells (WBC): 5,400 cells/µL
  • Red blood cells (RBC): 4.22 million cells/µL (low)
  • Hemoglobin (Hgb): 14.8 g/dL
  • Hematocrit (Hct): 42.8%
  • Mean corpuscular volume (MCV): 99.8 fL (high)
  • Mean corpuscular hemoglobin (MCH): 34.7 pg/cell (high)
  • Mean corpuscular hemoglobin concentration (MCHC): 34.7 g/dL
  • Red cell distribution width (RDW): 17.2% (high)
  • Platelets: 66,000 cells/µL (low)
  • Mean platelet volume (MPV): 8.3 fL
  • Partial thromboplastin time (PTT): 18.7 sec (high)
  • International normalized ratio (INR): 1.5
  • Alpha-fetoprotein (AFP): 13.9 ng/mL (high)
  • Glucose: 87 mg/dL
  • Blood urea nitrogen (BUN): 14 mg/dL
  • Creatinine: 1.0 mg/dL
  • Sodium: 129 mmol/L (low)
  • Potassium: 4.2 mmol/L
  • Total bilirubin: 2.8 mg/dL (high)
  • Direct bilirubin: 1.0 mg/dL (high)
  • Protein: 6.2 g/dL
  • Albumin: 2.4 g/dL (low)
  • Calcium: 8.0 mg/dL (low)
  • Aspartate aminotransferase (AST): 115 U/L (high)
  • Lactate dehydrogenase (LDH): 254 U/L (high)
  • Alkaline phosphatase (ALK): 156 U/L (high)
  • Alanine aminotransferase (ALT): 45 U/L
  • Gamma-glutamyl transpeptidase (GGT): 88 U/L (high)

Imaging study (April 6,2006): There was fatty infiltration in the liver. There was no evidence of space-occupying lesion or intrahepatic bile duct dilatation in the liver. There was ascites in the right upper quadrant of the abdomen. The gallbladder was normal. The kidneys were unremarkable. The spleen measured 16 cm in length, which indicated splenomegaly.

Past medical history: Hypertension; headaches; allergic rhinitis; depression and anxiety; substance abuse in remission

Medications: Hydrochlorothiazide, gabapentin (300 mg, 1 tab three times daily), loratadine (10 mg daily), steroid nasal spray daily; Aldactone (50 mg twice daily), Paxil(40 mg daily), trazodone (50 mg at bedtime)

Allergies: Penicillin

Physical examination: Vital signs within normal limits; weight: 155.2 lbs; mild icterus of the sclera; muscle wasting in the temporal area, upper extremities, and torso; abdominal fluid wave; caput medusae; small umbilical hernia; no lower extremity edema

Discussion

Question 1: This patient is extremely motivated to start treatment, but the literature states that treatment is not recommended in individuals with decompensated liver disease. Are there any options for this patient in regard to treatment outside the research arena?

Speaker 1: In review, we have a 54-year-old white man with chronic hepatitis C. He has genotype 1 HCV with a viral load of 128,400 IU/mL. He has a normal ALT level, but his AST level is 2 times the upper limit of normal, without alcohol use. He has not been considered a hepatitis C treatment candidate for a couple of years secondary to depression and anxiety. Recently, he has been doing well. The psychiatrist now says the patient is OK for hepatitis C treatment, and he comes to liver clinic. But, at this point, he has worsening liver disease. He would not submit to a liver biopsy and therefore HCV Fibrosure was done, yielding a fibrotic score of 0.97, or F4 cirrhosis. But, in my opinion, it was not appropriate to perform a liver biopsy because his physical exam had already revealed ascites (as we'll see in a minute when we look at the case in more detail). So frankly, I do not think he needed a biopsy or the Fibrosure test.

Let's look now at his lab results. Significantly, he has a platelet count of 66,000, an INR of 1.5, and an alpha-fetoprotein that is 13.9. He has a total bilirubin of 2.8, and an albumin of 2.4. So, you look at the Child-Pugh score for this patient. He apparently does not have encephalopathy, so that is 1 point. But, he does have ascites, so that's 2 points. He has an INR of 1.5, which is 1 point. He has a bilirubin of 2.8, which gives him 2 points, and an albumin of 2.4 that gives him 3 points. So, he has a Child-Pugh score of 9 (the upper end of Class B). Therefore, this patient actually needs a transplant more than anything else, right? He is already a decompensated cirrhotic patient, so that is really where we are. Unfortunately, his depression and anxiety had previously prevented him from getting therapy and now we're confronted with decompensated cirrhosis. He came to us after the psychiatrist said he was able to undergo treatment, but at this point we can see from the ultrasound that he now has ascites and splenomegaly.

His medications are hydrochlorothiazide, gabapentin, loratadine, steroid nasal spray, Aldactone, Paxil, trazodone. This indicates that he's already on diuretic treatment for his ascites.

On physical exam, he has mild icterus, muscle wasting in the upper extremities and torso, ascites, caput medusae, small umbilical hernia, and no edema. Decompensated cirrhosis is a very obvious diagnosis with these clinical findings.

Now we are confronted with a dilemma. This patient is extremely motivated to start treatment, but the literature states that treatment is not recommended for this patient because he has decompensated liver disease. Are there any options for antiviral therapy for this patient when he is referred to you in a decompensated state?

Let's all discuss this case. One group here responds and says that they would want to evaluate for liver transplant, and I agreed with that.

Question 2: Would anybody have something else to say about evaluating this patient for a liver transplant as the number one thing to do?

Participant: If this patient chose not to submit to a liver biopsy, should we be concerned about this refusal? Can we expect that this will be a patient who is compliant with going through all that is entailed in a liver transplant if he was not willing to go through just a liver biopsy?

Speaker 2: I agree. Clearly, this patient has refused to have a biopsy, and that is much less involved than a transplant. I would be concerned that the patient's degree of motivation has to be taken into account.

Speaker 1: He has decompensated cirrhosis, and he has genotype 1 HCV. According to the Everson dataLink will take you outside the VA website., he has a 13% likelihood of achieving a sustained virological response (SVR). Without an SVR pretransplant, he will have HCV recurrence posttransplant. So, is it worth it? Is it worth the expense? You're going to have to treat him for one year, and treat him with growth factors, for well over $70,000, with only a 13% chance of an SVR. Is this worth it?

Question 3: What if I can convert this patient from a decompensated state to a compensated state?

Speaker 1: Well, that is essentially only possible if your patient is also still drinking alcohol. In that situation, you have a patient with both acute and chronic liver disease. If your patient has components of alcoholic hepatitis with ascites and encephalopathy, and that patient stops drinking, then the patient can go from a decompensated to a compensated state. You definitely treat the hepatitis C if the patient becomes compensated. But that only happens if the decompensation was a result of drinking. Otherwise, in terms of decompensation, I have treated patients who have had variceal hemorrhages, but not those who have had ascites. In this particular case, I would hold off with any hepatitis C therapy. I would send him for a liver transplant evaluation and would also screen for varices. He's already had an ultrasound screening for hepatocellular carcinoma.

Speaker 2: You point out that there is one group of patients who have an element of alcoholic hepatitis and, with cessation of drinking, you will see these people often improve clinically. Another group that could clinically improve is patients with hepatitis C and untreated hepatitis B. These patients--particularly if they come in with high transaminase levels, deteriorating liver function, and decompensated cirrhosis--can also clinically improve with treatment of their hepatitis B.

Speaker 1: You are exactly right. For example, I do have one patient who was not decompensated but did have varices. He had compensated cirrhosis and we treated him. He could tolerate just 3 months. He got an SVR with just 3 months of therapy, which is incredible, but his varices actually disappeared. So, there is some merit to this assumption: If we had therapy for hepatitis C that was effective and would not leave patients vulnerable to further decompensation, a reversal from decompensated to compensated state could be achieved if the etiologic factor (the hepatitis C) were reversible. I would agree with that, but we have no evidence that we're actually doing this in treating hepatitis C with interferon and ribavirin. Also, getting rid of the ascites doesn't really mean that the cirrhosis is compensated.

Speaker 3: At my table, we were talking about whether we would treat this patient. The real issue with his risk of decompensation is that, if you stimulate his T-cells to go after his hepatitis C, all of a sudden they kill his 8 remaining hepatocytes, his bilirubin goes to 5, and he becomes encephalopathic. That's the concern and the basis for a decision not to treat, right?

Speaker 1: That's it.

Speaker 3: I have a question about a referral for transplant. Where does this person stand with respect to transplant timing? We calculated this patient's MELD score to be 15. So, the other question for our transplant centers is, "Do you want to see this patient now? At what MELD score should we be thinking of referring?"

Speaker 2: Well, I think a MELD score higher than 8 or 9 is in the range for referral. So, yes, I think that you should be beginning to prepare the patient for transplant and should be educating him about how to take care of his cirrhosis. You're treating him, but you're not treating him with interferon.

Question 4: Suppose this man instead had genotype 2b and a low viral load, and had been referred for transplant. Would you treat him?

Speaker 2: Maybe. If he were genotype 2 and his ascites was responding very well to only 50 mg BID of Aldactone, I might give a trial of low-dose therapy. But, I know that only 50% of nongenotype 1 patients achieved an SVR with the low-dose regimen in a studyLink will take you outside the VA website. of these decompensated patients by Everson.

Question 5: What if the patient has genotype 2 but has refractory ascites?

Speaker 1: Refractory ascites would be different. If the patient is not responsive to diuretics, we're in another totally different category and giving antiviral therapy in such circumstances is just wasting time and resources.

Now, what if this patient only needs minimal doses of diuretics and totally gets rid of the ascites, but his albumin is still only 2.4? I'm still hesitant to treat this sort of patient because I'm more afraid of harming him with antiviral therapy than eager to find out what the benefits are going to be. If he were genotype 1, I definitely would not start treatment. If he were genotype 2 and responding fairly well to diuretics, I might consider treatment but still would be very uneasy. I am very cautious because I don't want to worsen infections or accelerate decompensation.

Speaker 2: I think that's a good point. In the studies that attempted antiviral therapy in people with Child-Pugh scores with a mean of 11, there were deaths from infections, the therapy was poorly tolerated, and nobody cleared virus. Later protocols were based on people with lower Child-Pugh scores--just into the range of cirrhosis, where you're beginning to think about transplant. That's a different group.

Speaker 1: Absolutely.

Speaker 2: I also think you need to keep in mind that you can treat these patients after transplant. Yes, there is a risk from hepatitis C during transplant, but it only adds about 5% to your 5-year mortality. Most patients with hepatitis C can be managed. Yes, it does mean long-term cirrhosis. But treatment before transplant is not your only option.

Speaker 1: I totally agree with that. In the case we have discussed here, the consensus is that we would not give antiviral therapy. Is anybody opposed to this?

Participant: Actually, we had a question at my table. If you did get this patient listed for transplant and he was genotype 2, and you felt the ascites was controlled well enough for pretransplant treatment, would you advocate treating him locally or would you refer him to a transplant center and have his treatment managed there? What if the transplant center was a very long distance away?

Speaker 1: Although that would be ideal if there were resources, it is usually not feasible to transfer patients long-distance for all their pretransplant care.

Participant: The fact that the patient in this case doesn't want a liver biopsy seems to be a predictor of more psychiatric-related problems and suggests that he is not such a great candidate for transplant. Could the transplant specialists here comment on that?

Speaker 3: When we evaluate patients who do not want invasive procedures, we don't know how the physician presented the idea to the patient. In this particular case, we can't really tell whether the patient's depression and anxiety is really under control based on his refusal for liver biopsy. We need to know about his compliance in general. Maybe his physician said, "You know, you've got hepatitis C and we don't know what your histology is. Maybe we should get a liver biopsy," and then the patient said, "No, no. I really don't want one if I don't need it." This is different from a patient who won't take his spironolactone and won't come to the clinic visits. So I wouldn't hold against him the fact that he didn't want a liver biopsy if everything else is OK.

Speaker 1: At our center, we specifically target patients who have active mental health issues. This patient has been prepared by a psychiatrist for a course of antiviral therapy. We have found that, if these patients can be followed closely by their psychiatrists, they are able to complete antiviral therapy as well as patients who do not have an active mental illness. So in that sense, I think if you can keep these patients well controlled, mental illness should not be a contraindication for either antiviral therapy or transplant.

Summary Points

  1. Patients with compensated cirrhosis are candidates for treatment and should be considered for treatment with some urgency so that treatment can be instituted before decompensation begins.
  2. Patients who have decompensated cirrhosis are not suitable for antiviral treatment for hepatitis C because of the risk of infections and further decompensation--such as inducing encephalopathy and worsening ascites.
  3. Patients who have decompensated cirrhosis also should not be treated because they have a very low likelihood of treatment response.
  4. Treatment of a cirrhotic patient is important if the patient needs a transplant in the future--it is ideal to achieve an SVR pretransplant in order to reduce the likelihood of posttransplant HCV recurrence.
  5. If a patient is already decompensated, calculate the MELD score and refer for a liver transplant evaluation if the score is 8 or above (or check with your transplant center).
  6. If there are components of the decompensation that are cause by alcoholic hepatitis, you may be able to convert the patient to compensated cirrhosis with cessation of drinking.
  7. Controlling ascites with diuretics does not mean you have converted the patient to a compensated state.

Facilitators/Speakers

  • Ann Busch, Liver Transplant Clinical Nurse Specialist, Portland VAMC
  • Sue Currie, Associate Director, HCRC, San Francisco VAMC
  • Guadalupe Garcia-Tsao, Director, HCRC, Connecticut VAMC
  • Douglas Heuman, Liver Transplant Program Director, Richmond VAMC
  • Alexander Monto, Director, HCRC, San Francisco VAMC
  • Roberta Ruimy, Manager, Liver/Kidney Transplant Programs, Portland VAMC
  • Brenda Salvas, Health System Specialist, Manager, Liver and Kidney Transplant Program, VA Transplant Program, VA Central Office, Washington, DC
  • Anna Sasaki, Staff Physician, Portland VAMC
  • Kristine Stick, Nurse Practitioner for Hepatology, San Francisco VAMC
  • Suchat Wongcharatrawee, Associate Director HCRC, Connecticut VAMC

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