for Health Care Providers
4: A patient with compensated cirrhosis, diabetes, bipolar disorder, and alcohol relapses: Would you retreat? Would you use beta-blockers for prophylaxis of variceal bleeding?
A 51-year-old married Caucasian male has chronic hepatitis C virus (HCV), genotype 1, and compensated cirrhosis. He was treated in 2001 in a private practice with pegylated interferon and ribavirin for 3 months, whereupon his insurance would no longer pay for the medications and the treatment was stopped. In 2004, he began receiving care at the VA Liver Clinic and treatment was started again for 8 weeks, but discontinued because of an exacerbation of his bipolar disorder. At this point, the patient is eager to have his HCV re-treated.
The severity of the patient's cirrhosis is currently categorized as Class A on the Child-Pugh scale, with a score of 6 using the Model for End-Stage Liver Disease (MELD) system. Additional studies have included a triple-phase computed tomography (CT) scan of the abdomen showing 2 stable, 5 mm cysts and mild splenomegaly, but no focal liver lesions or ascites. Ultrasound scanning of the liver showed moderate hepatomegaly with a coarse bright echo pattern, and the Doppler mode indicated a normal portal system. An esophagogastroduodenoscopy (EGD) procedure revealed no gastric or esophageal varices.
His other medical conditions include diabetes mellitus, which is poorly controlled. He is insulin dependent and has a hemoglobin A1c level of 12.8%. A clinical nurse specialist monitors him to optimize his diabetes management. He also has extreme obesity, with a body mass index (BMI) of 41.
The patient also has bipolar disorder and post traumatic stress disorder. Psychiatrists at the VA monitor him closely for bipolar management and medication adjustments. After a period of stability and evaluation, they have now cleared him for another round of HCV treatment.
In addition, the patient has a long history of alcohol abuse, with periodic relapses from sobriety, during which intermittently low platelet counts have been noted. He has been abstinent for 6 months, after a suicide attempt with benzodiazepines and alcohol resulted in hospitalization.
The VA Liver Clinic chose to re-treat him and recently started him back on pegylated interferon and ribavirin.
- Pegylated interferon-alpha 2a: 180 mcg via subcutaneous injection, once weekly
- Ribavirin: 1,200 mg orally, once daily
- Insulin (neutral protamine Hagedorn [NPH]): 24 units via subcutaneous injection, twice daily
- Metformin: 1,000 mg orally, twice daily
- Propranolol: 40 mg orally, twice daily
- Citalopram: 20 mg orally, once daily
- Lamotrigine: 150 mg orally, twice daily
- Clonazepam: 1 mg orally, 4 times daily
- Quetiapine: 200 mg orally, at bedtime
- Terazosin: 5 mg orally, at bedtime
- White blood cell (WBC) count: 3,820 cells/µL
- Red blood cell (RBC) count: 3.91 million cells/µL
- Hemoglobin count: 12.5 g/dL (low)
- Hematocrit percentage: 36.8% (low)
- Platelet count: 122,000 cells/µL (normal)
- Albumin level: 3.4 g/dL
- Aspartate aminotransferase (AST) level: 78 U/L (down from 130 U/L within 4 weeks of starting HCV treatment)
- Alanine aminotransferase (ALT) level: 92 U/L (down from 135 U/L within 4 weeks of starting HCV treatment)
- Total bilirubin level: 0.6 mg/dL
- Thyroid stimulating hormone (TSH) level: normal
- Glycated hemoglobin (A1C) level: 12.8%
- Alkaline phosphatase: unknown value
- International normalized ratio (INR): 0.94
- HCV viral load: 3.08 million virus equivalents/mL
- Creatinine: 1.1 mg/dL
- Alpha-fetoprotein: 10.2 mcg/L
Question 1: For a cirrhotic patient with these comorbid conditions, under what circumstances would you retry HCV treatment?
Speaker 1: We would now classify this patient's condition as Stage I; he has compensated cirrhosis, with no varices. But with these comorbidities, does anyone disagree with the decision to restart this man on pegylated interferon and ribavirin?
Speaker 2: Yes, I do. Although he is clinically compensated, the albumin level low at 3.4 g/dL. So where does that put us in terms of predicting his mortality?
Speaker 1: You are correct. This albumin measurement is not consistent with what is being described in terms of the liver disease. His other laboratory results, such as the INR of 0.9 and the bilirubin level of 0.6 mg/dL, are not consistent with the low albumin measurement of 3.4 g/dL. In this case, the low albumin may be caused by reasons other than this liver disease--because he is diabetic, I would check his urine to see whether he has albuminuria; otherwise, you are correct, the albumin level is too low, and that would be a factor for predicting decompensation.
Speaker 2: Right. And, he has several competing diseases. Let's consider the diabetes. With a hemoglobin A1c percentage of 12.8 and obesity, his risk of dying of a heart attack or renal disease within 5 years is probably greater than his risk of dying from cirrhosis. He would need to manage the diabetes much more successfully before I would put him on interferon, which might actually worsen the diabetes during treatment.
His psychiatric disorder makes him extremely high-risk, despite his desire for treatment. Weighing the risks, his psychiatric diseases are at least as important as his hepatitis C. Because undergoing treatment could destabilize him mentally, the existing psychiatric issues would need to be very carefully managed before I would even consider adding interferon treatment, which could put him at risk of suicidality.
Speaker 3: Another point is that the patient has hepatitis C and a history of alcohol abuse. We know that a large group of patients with hepatitis C have indolent liver disease, but when someone has hepatitis C, a history of alcohol abuse, and cirrhosis, it is usually assumed that hepatitis C is the cause of the cirrhosis. However, I think there are some people in whom the alcohol has been the cause of the cirrhosis, and when they stop drinking, they go back to having indolent disease. There are no recommendations for trying to sort this out and differentiate the effect of the alcohol on the cirrhosis, though the alcohol factor is treatable with abstinence. We tend to be fairly aggressive and focus on treating hepatitis C in cirrhotic patients. But, with situations in which the patient stops drinking and has normalization of transaminases, it may be worthwhile to perform a biopsy to see how much of the liver is really active. This may be a beneficial strategy for patients such as this one, with whom you might not want to be terribly aggressive about treating because of the numerous high-grade relative contraindications to therapy.
This particular patient probably has active hepatitis C driving the liver disease, as his high transaminase levels decreased in response to treatment, so such a consideration is not applicable to his case. But I did want to point out that we can be overly aggressive about treating people with fibrosis and hepatitis C, without considering whether the fibrosis is actually caused by the hepatitis C.
Speaker 1: I totally agree.
Speaker 3: Another point is that bipolar disorder can be very challenging in the setting of treatment, which, along with this patient's history of suicide attempts, certainly puts him into an extremely high-risk category. I think it is reasonable to assess whether the patient is too high-risk for treatment. If his bipolar disorder is deemed to be under careful control, the decision regarding whether to restart therapy is a judgment call for the treating physician.
Speaker 4: In advising this patient, how would you assess his chances of achieving a sustained virologic response (SVR), given that therapy would be re-treatment and that he has HCV genotype 1, a high viral load, cirrhosis, and a high BMI?
Speaker 1: I would say 10-20%.
Speaker 4: Does anyone else agree?
Speaker 2: I'm being generous, actually. It's 10%.... I would quote 10% to the patient and then talk to him and make him realize that he could have side effects. He already had an exacerbation of psychiatric disorder. I believe there would be a 10% chance of SVR--in the best of cases. So, yes, the chances of his virus responding to treatment are extremely low.
Speaker 2: First, we have to define our goals of treatment, in terms of antiviral therapy for a compensated cirrhotic patient.
Speaker 1: Let me provide some data to help us. Can the use of antiviral therapy for patients with compensated cirrhosis prevent hepatocellular carcinoma (HCC), decompensation, or death?
In a recent study whose findings were published in Hepatology, researchers followed patients who had compensated cirrhosis and were treated with either interferon or interferon and ribavirin. They found that decompensation was eliminated in those patients for whom an SVR was achieved. And that really is the goal. HCC incidence was also significantly lower among patients who experienced an SVR. And the survival rate among patients with an SVR was improved. So, our goal of treatment would be to achieve an SVR in order to reduce decompensation, HCC, and death. Now, what is the likelihood of achieving an SVR with the patient in this case? It is in the realm of 10%.
Speaker 2: We should also ask whether there is a role for maintenance therapy in the event an SVR is not achieved. When I see patients such as this one, I realize there is a very small chance of an SVR, but I might consider maintenance therapy for many of them for suppression on long-term but low-dose treatment. Now, we would like to hear from the participants.
Participant: We may have treated him at some point, but our biggest concern was his weight and his diabetes, which would need to be brought under better control before the initiation of treatment. We also considered whether this patient would be a candidate for liver transplant if he were to receive treatment and go from the compensated to decompensated state. But we would first need to have a discussion with the patient to determine whether he would want a transplant in the event his condition worsened. If so, would he even be a candidate? We did not feel that he would have been, given his alcohol abuse, prior suicide attempt, and other mental health aspects.
Speaker 1: So you would wait until he lowers his BMI to what?
Participant: We didn't decide on a specific number.
Speaker 1: OK, but you would want him to show at least some degree of weight reduction?
Participant: Let's say loss of 10% of body weight.
Speaker 1: All right, let's discuss it with another group.
Participant: We came to a similar conclusion with this patient, but we discussed how long we would wait before reevaluating him. Some said 3 months, some said 6 months, but we would not consider him for treatment at present.
Participant: Our group concluded that we would not treat him right now because of the potential adverse effects of treatment on his comorbidities. And we certainly would not treat him unless he were totally cleared by psychiatrists. The patient would need a 1-year course of treatment, so we would not know whether an SVR had been achieved for a year and a half, which is a long time for this patient. If we were to treat, we would check the HCV RNA with polymerase chain reaction (PCR) testing after 4 weeks to see whether he had a response. Regarding the option of a transplant, we were in slight disagreement. Some members of the group felt he might be a candidate, even though it would require 6 months to demonstrate that he had abstained from alcohol, lost weight, improved diabetes management, and addressed his mental health issues. But we would not totally exclude him from the option of transplant. At the same time, we believe he should be screened for HCC at 6, 9, and 12 months. If we do see cancer, the patient should have the option of addressing that during the 6 months he is getting sober and managing his other issues.
Speaker 4: As for transplantability, the patient is not a candidate at this point for many reasons. Because of his comorbidities, the BMI must be 35 or less. Not only must he be 6-months sober, he also has to successfully complete an alcohol treatment program and be involved in aftercare and relapse prevention. Of course, his bipolar disorder is not under control either.
Moderator: There are different BMI cutoffs at different VA centers. The maximum BMI for transplantability is 40 at Pittsburgh, 35 at Portland, and 35 at Nashville.
Another question was just raised: "How do you determine BMI for someone who has ascites and edema?"
Speaker 2: The effect of even massive obesity on posttransplant mortality is relatively modest. The effect on respiratory complications, length of hospital stay, and wound complications, however, is not modest. It is quite striking. But selected obese patients can be pulled through transplant, and I think it is not necessary to have a fixed BMI cutoff. By and large, somebody with a BMI over 40 is not going to be listed for transplant. If the BMI is between 35 and 40, we are willing to look at the patient, assess what else is involved, and factor in water weight and other things. But this patient clearly would be better off at a lower weight.
Participant: In general, it's the same in every case. If the patient has a BMI of 40, and he is fairly active and in decent shape, he will probably do well. But if a patient is in the intensive care unit on a ventilator or is extremely sick, with MELD scores as high as 35 or 36 and a BMI of 38, you know he simply is not going to do well.
Speaker 1: At this moment, this patient is not a transplant candidate because of his liver disease! He has a MELD score of 6. His only low value is the albumin level, and we wonder whether that is because he is losing it through his urine. But if the low albumin level is attributable to liver dysfunction, I agree entirely that he is nearing decompensation and that he has to move quickly in terms of getting into a weight reduction program, alcohol rehabilitation, and so forth.
Participant: This patient is grossly overweight, has diabetes, and continues to drink on top of that. I think that many of us would never consider treatment. The focus should not be on his hepatitis virus; that is very low on the list of his real problems. He needs very strict, very supportive psychiatric evaluation and therapy.
Participant: I don't think we have a consensus, but we all agree that this is a difficult-to-treat patient. Half of us are perhaps willing to try treatment, for the simple reason that the patient is 51 years old and already has cirrhosis; we have nothing else to offer him.
Participant: Considering that 70% of patients with diabetes would die from cardiovascular disease such as myocardial infarction, heart attack, or stroke, I wonder whether we could use the Framingham equation to calculate this patient's cardiovascular risk? If the patient has more than 20% risk of dying from cardiovascular event, then we should not start him on hepatitis C treatment. But we cannot calculate his Framingham risk score because we do not know whether he is a smoker, and we have no data on his systolic blood pressure or cholesterol levels.
Participant: For me, the most important issue here is awareness of the competing risks. This is a 51-year-old patient; some physicians would not treat him without first obtaining results from a stress test. But, it is a fact that he has competing risks. It is important to understand each competing risk and to be aware that initiating treatment can increase those risks, perhaps even precipitating a coronary event. It is necessary to determine whether a patient such as this one is a transplant candidate, because no one benefits if a patient who is fairly well compensated, with good 5-year survivability odds, becomes decompensated on therapy. Predicting which patients will decompensate is difficult, but it is very clear that this patient would not be a candidate at many centers. His BMI is too high, his diabetes is out of control, and he has not addressed competing risks. When somebody comes in with a pack of cigarettes in a shirt pocket and says, "Doctor, you must treat my hepatitis C," that person is more concerned about something that isn't as risky as what's right there in the shirt pocket. And you have to deal with the fact that treating the hepatitis C could exacerbate other risks that are probably going to kill them, but probably not for another 5 years or so.
Speaker 1: How many cirrhotic patients that you have treated for hepatitis C actually decompensated on therapy?
Participant: The patients that decompensate on treatment are usually somewhat sicker than this patient, in fact. If this patient were to decompensate on treatment, and the matter were taken to court, you would be asked: "What were you trying to accomplish with this man? How could treatment have helped this patient?" You could argue that there is benefit from maintenance treatment with normalization of his transaminases and benefit in HCC prevention.
Speaker 1: With the available data, we can calculate his odds of surviving with cirrhosis for 5 years at between 60% and 70%.
Participant: Our group had a consensus that we would not consider this patient for treatment immediately. He would need better management of his comorbidities, particularly the diabetes and BMI. We would need to determine how his sobriety and psychiatric follow-up would occur. If we were to treat him, we would look at his past treatment history and any viral response he had. If there were no response, there would probably be no reason for re-treating because the chance of a complete response would be zero, considering all his comorbidities. But if he had good early viral kinetics in his previous treatment, we would consider re-treatment with a caveat that he have weekly mental health follow-up to make sure he was adhering to therapy reasonably, and we would check virologic response at 4 and 12 weeks. If there were any indication of nonresponse, we would stop treatment very early.
We feel this patient has a very poor chance of ever being a transplant candidate--even though he doesn't need a transplant yet--and that is why it may be worth initiating re-treatment, even though we estimate the chance of an SVR at 10%. So, we would weigh the potential benefit to the patient against the very small risk of causing decompensation or worsening comorbidities. With the use of early viral kinetics, we could determine early on into his retreatment course whether it would be worthwhile to complete the entire 48 weeks.
Question 2: Would you use beta-blockers for prophylaxis of variceal bleeding?
Speaker 1: For this patient, he may be receiving propranolol for cardiac reasons rather than variceal prophylaxis. If propranolol was chosen for hypertension or cardiac prevention, you may save him a screening endoscopy, all right? But if he is on propranolol for the purpose of prophylaxis for varices, you should optimize the dosage. The propranolol dosage at which we initiate treatment for varices is 20 mg twice daily. After 1 week, we double the dosage to 40 mg twice daily, if the patient's heart rate is more than 60 beats per minute. If the heart rate is stable, we continue to increase the dose by adding 20 mg for the morning dose and 20 mg for the evening dose, repeatedly, until we get to the dosage at which the heart rate is between 55 and 60.
The reason to do a screening endoscopy is to decide whether to add propranolol or other beta blockade. But if you have then chosen to include propranolol for treatment of hypertension and you then optimize the dosage for variceal prophylaxis at the same time, then there is no reason that you additionally need a screening endoscopy.
Participant: I have two points. First, you mentioned about performing routine screening endoscopy of all cirrhotics for varices. We've actually taken a somewhat different approach and, at our VA facility at least, we essentially empirically treat everybody with propranolol for suspected varices, in consideration of the cost benefits and the fact that propranolol is generally well tolerated in most patients.
The second point is that, among beta-blockers, propranolol is considered the most effective for variceal prophylaxis because it is the least cardio-selective. I would like to hear some ideas as to why it is therefore so important to adjust the dosage toward a target heart rate.
Speaker 1: Those are incredibly important questions. You definitely need nonselective beta-blockers: beta-1 and beta-2 blockers. So, that basically limits our choices to propranolol and nadolol. The main goal is to reduce portal pressures, the beta-2 effect. I was involved in studies that looked into a possible correlation between the decrease in portal pressure and the decrease in heart rate, and they found no correlation whatsoever. But, the reason we adjust dosages on the basis of heart rate is that we want to give patients the maximum dosage without inducing bradycardia, not because lowering the heart rate would have an effect on portal pressure. It might not. In an ideal world, one would want to administer the beta-blocker and then measure the portal pressure. However, because the procedure is invasive, no one would choose that option, especially for primary prophylaxis. Thus, a beta-1 and a beta-2 blockade would be preferable, and the reason for monitoring heart rate is that it is measurable in the clinic and doing so allows for administration of the maximal dosage while avoiding adverse effects.
As for the second issue--the question of universal beta blockade--50% of patients will not have varices, and less than that will actually have large varices upon screening. In a large multicenter, double-blind study of patients who had cirrhosis with measured portal hypertension but no varices, subjects were randomized to placebo or beta-blockers to determine whether beta-blockers could prevent the development of varices. Funded by the National Institutes of Health, the study was a negative study: There were no differences between atenolol (a nonselective beta-blocker) and placebo.
Therefore, using beta-blockers universally without first testing for varices would amount to overtreating. Patients usually prefer not to be treated unless it is necessary. They don't like to feel fatigued, and the main reason patients do not choose beta-blockers is that they are afraid of being fatigued and afraid of becoming hypotensive or experiencing shortness of breath. So, using beta-blockers universally would result in overtreating among more than half of the patient population with something that gives them side effects. That makes no sense to me. The cost-efficacy studies were done before the randomized trial showed no efficacy in using beta-blockers for someone who does not have varices.
Speaker 4: I completely agree with you, and my patients tolerate beta-blockers very, very poorly. In addition, this particular patient has depression and he has insulin-dependent diabetes. Endoscopically, he has no varices. So, one would question why he is being treated with beta-blockers.
Speaker 1: I agree with you entirely. I have no idea why this patient is on propranolol. If it is being used for primary prophylaxis, that is totally wrong--we do not recommend using beta-blockers if varices have not yet developed.
Participant: You mentioned a tendency to start patients on propranolol at a dosage of 20 mg twice daily. Many of our patients have trouble with their beta-blocker, so we tend to start at 10 mg twice daily. Also, I don't think I have any patient taking 40 mg twice daily.
Speaker 1: In the trials for primary prophylaxis, we start at around 40 mg twice daily. I am more conservative and start patients at 20 mg twice daily, but I still pay much attention to their baseline blood pressure to determine whether they can tolerate it and to see much we can increase the dosage. But I typically start at 20 mg twice daily and monitor their heart rate and blood pressure weekly to determine whether they have symptoms. We teach patients how to check their own pulse as well. When possible, we will increase their dosage.
Participant: I have heard that patients who start, stop, and restart treatment with beta-blockers have more problems than those who are never put on beta-blockers at all. Patients may have trouble getting prescriptions and go through periods when they are on and off the medication. That concerns me.
Speaker 1: You are correct, and I share your concern. Trials comparing beta-blockers and ligation have found that ligation did precipitate bleeding in a couple of patients, and I would not choose ligation if I were a patient. There were patients in the beta-blocker arm who experienced bleeding, but these events all occurred after the patients had totally stopped taking the beta-blockers. So, variceal hemorrhaging can occur if the beta-blocker is discontinued suddenly. With patients for whom you intend to initiate ligation because they cannot tolerate beta-blockers, I would recommend overlapping the two treatments instead of abruptly stopping beta-blockers and then switching to ligation.
Participant: I have encountered many gastroenterologists who are hesitant to perform endoscopy on patients with cirrhosis, but you have recommended endoscopy for every patient with cirrhosis. When EGD is not available, and in the absence of data to indicate whether varices are already present, the next-best option must be universal beta blockade. Would you agree?
I also wanted to know about the use of metalol as opposed to propranolol, given that metalol is administered once daily at bedtime. What is your opinion about metalol?
Speaker 1: Metalol is not on formulary at the VA, but I definitely would use metalol. It has less of a central nervous system effect, so, if a patient becomes very depressed on propranolol, you should switch them to metalol. Metalol is also more convenient for patients because, as you mentioned, they just have to take it once a day, and the dosage is the same as that for propranolol, starting at 20 mg daily.
- When considering re-treatment for a patient, consider whether there were conditions of the prior treatment course which could be improved in the re-treatment course to increase the chance of achieving an SVR. In the current case, 2 prior treatment courses were of inadequate duration. Therefore, the need for an adequate trial with the optimal duration of 48 weeks is a reason to consider the benefit of re-treatment.
- Estimate the chance that an SVR will be achieved with re-treatment. In the current case, the speaker estimated there was a 10% chance of SVR with re-treatment.
- Estimate the chance that the patient could be harmed from retreatment--in terms of decompensation of cirrhosis or exacerbation of other comorbid conditions (bipolar destabilization or worsening of diabetes). Carefully consider whether destabilization of other health conditions could be more harmful to the patient than untreated hepatitis C.
- If the chances of decompensation or risk of exacerbating other conditions is more significant than the risk of not re-treating (leaving the hepatitis C in a viremic state), then it may be best to optimize the other medical conditions before initiating another course of hepatitis C treatment.
- When managing a patient who has established cirrhosis, a screening endoscopy is recommended for the early detection of varices. If varices are detected, secondary prophylaxis with propranolol is recommended with a starting dosage of 20 mg twice daily and up-titration to a heart rate of approximately 60 BPM or as tolerated.
- If a patient has cirrhosis and needs a beta-blocker for another reason such as hypertension or coronary artery disease, and if propranolol is the chosen beta-blocker, performing the screening endoscopy can be avoided because the beta-blocker of choice is already being used.
- If the patient has no other indication for a beta-blocker, perform a screening endoscopy to determine whether a beta-blocker is necessary instead of using beta blockers for all cirrhotic patients, which would include many patients who have not developed varices.
- Sue Currie, MA, Epidemiologist, Associate Director, San Francisco, HCRC
- Alexander Monto, MD, Hepatologist, Director, San Francisco, HCRC
- Guadalupe Garcia-Tsao , MD, Hepatologist, Director, Connecticut, HCRC
- Joseph Awad, MD, Liver Transplant Program Director, Nashville VAMC
- Anna Sasaki, MD, Hepatologist, Portland, VAMC
- Thomas Cacciarelli, MD, Liver Transplant Program Director, Pittsburgh VAMC
- Brenda Salvas, Senior Program Manager, VA National Transplant Program
- Douglas Heuman MD, Liver Transplant Program Director, Richmond, VAMC
- Bashar Aqel, MD, Hepatologist, Minneapolis, VA, HCRC
- HoChong Gilles, RN, MS, FNP, Clinical Coordinator, Richmond, VAMC
- Kristine Stick, NP, Liver Transplant Coordinator, San Francisco VAMC
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