John B. Gross

Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration

Background: Copper deficiency in ruminants is known to cause an ataxic myelopathy. Copper deficiency as a cause of progressive myelopathy in adults is underrecognized. Objective: To describe the clinical, biochemical, electrophysiologic, and imaging characteristics in 13 patients with myelopathy associated with copper deficiency. Methods: The records of patients with a copper deficiency–associated myelopathy were reviewed. Clinical characteristics, laboratory investigations, and responses to therapeutic intervention were summarized. Results: Thirteen such patients were found, 11 of them in a 15-month period. All patients presented with prominent gait difficulty, reflecting a sensory ataxia due to dorsal column dysfunction and lower limb spasticity. All patients had polyneuropathy. A high or high-normal serum zinc level was seen in 7 of the 11 patients for whom this information was available. Somatosensory evoked potential studies done in eight patients showed impaired conduction in central proprioceptive pathways. Dorsal column signal change on spine MRI was present in three patients. An initial clue to the diagnosis was a very low ceruloplasmin level; further tests of copper metabolism excluded Wilson disease. The cause remained unexplained in most patients. Oral copper supplementation restored normal or near-normal copper levels in 7 of the 12 patients in whom adequate follow-up data were available; parenteral supplementation restored normal level in 3 further patients. Copper supplementation prevented further neurologic deterioration, but the degree of actual improvement was variable. Conclusions: Unrecognized copper deficiency appears to be a common cause of idiopathic myelopathy in adults. The clinical picture bears striking similarities to the syndrome of subacute combined degeneration associated with vitamin B12 deficiency. Early recognition and copper supplementation may prevent neurologic deterioration.

Liver resection and cyst fenestration in the treatment of severe polycystic liver disease

BACKGROUND/AIMS There is limited information on treatment options for massive, highly symptomatic polycystic liver disease. The aim of the study was to analyze the immediate and long-term outcome of combined liver resection and fenestration. METHODS Information was abstracted from medical records. Follow-up was obtained by mailed questionnaire. Liver volume was quantified by computed tomography. RESULTS Thirty-one patients underwent liver resection and fenestration between July 1985 and June 1993. Mean liver volume was 9357 mL before and 3567 mL after surgery. There was one death from postoperative intracerebral bleed. Eighteen patients experienced complications, usually transient pleural effusions or transient ascites. Twenty-eight of 29 surviving patients with adequate follow-up have experienced immediate and sustained relief of symptoms and improvement in quality of life. After median follow-up of 2.4 years (range, 0.2 to 7.9 years), most patients have not had clinically significant enlargement of the liver. Sequential computed tomography scans before and after surgery suggest that hepatic enlargement in the age range of the patients in the study mainly resulted from the expansion of existing cysts rather than from the development of new cysts. CONCLUSIONS Selected patients with severe symptomatic polycystic liver disease and favorable anatomy benefit from liver resection and fenestration with acceptable morbidity and mortality. The extent of hepatic resection and fenestration is important for the long-term effectiveness of this procedure.

Cost-Effectiveness of 6 and 12 Months of Interferon-α Therapy for Chronic Hepatitis C

Hepatitis C virus (HCV) is a major cause of liver-related illness and death in the United States. A recent report from the Centers for Disease Control and Prevention [1] estimated that 35 000 to 180 000 persons develop HCV infection and more than 8000 die of HCV-related illness each year. One reason that hepatitis C continues to be an important public health concern is the lack of effective therapy to eliminate HCV. Despite an initial biochemical response in up to 76% of patients after 6 months of interferon- therapy, only about 10% achieve a sustained response (defined as disappearance of biochemical, histologic, and virologic evidence of chronic hepatitis C) [2-5]. An additional 5% to 7% of patients may attain a sustained response when treatment is extended to 12 months [5, 6]. Because of the low efficacy and high cost of interferon-, the cost-effectiveness of the drug in the treatment of chronic hepatitis C has been questioned [7]. One of the difficulties in evaluating the cost-effectiveness of interferon- is lack of clinical data. The long-term effectiveness of interferon- remains undetermined because follow-up in most studies has lasted no more than 1 year. The effect of interferon- on the development of decompensated cirrhosis and hepatocellular carcinoma is also unknown. Moreover, our understanding of the natural history of chronic hepatitis C without treatment is incomplete. Investigators have therefore relied on computer-generated models to evaluate cost-effectiveness [8, 9]. Previous analyses have suggested that 6 months of interferon- treatment yields substantial health care cost savings [8, 9]. We analyzed the cost-effectiveness of 6 and 12 months of interferon- treatment for chronic hepatitis C by using a computer model that incorporated prognostic variables associated with the progression of liver disease and response to interferon-. Methods Overview of Analysis We first used probabilities derived from an analysis of the current literature to construct a Markov model that describes the natural progression of liver disease from chronic hepatitis C in a cohort of patients. This model is described in detail in the Appendix. On the basis of this natural history model, we simulated a randomized treatment trial comparing no treatment, 6 months of interferon- treatment, and 12 months of interferon- treatment. The cost-effectiveness of interferon- treatment from the point of view of society was assessed by comparing the number of liver-related deaths, quality-adjusted survival, and costs among the treatment strategies. Simulations and analyses were performed and verified by using a statistical software package (SAS, SAS Institute, Cary, North Carolina) and spread-sheet software (Excel, Microsoft Corp., Redmond, Washington). Natural History Model for Chronic Hepatitis C Our Markov model consisted of six disease states: chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis, orthotopic liver transplantation, hepatocellular carcinoma, and death (Figure 1). The entry point of our model was chronic hepatitis C without cirrhosis, as determined by liver biopsy. As shown in Figure 1, patients may progress from chronic hepatitis C to compensated and decompensated cirrhosis over time. Compensated cirrhosis is diagnosed when the patient has histologically progressed to cirrhosis but has neither developed any symptoms nor required ongoing medical treatment. Once a patient experiences symptoms related to cirrhosis, he or she is classified as having decompensated cirrhosis and incurs expenses for health care services. Some patients with decompensated cirrhosis may develop hepatocellular carcinoma or undergo liver transplantation. As the population ages, an increasing number of patients die of natural causes independent of liver disease. We modeled four age-specific cohorts (30, 40, 50, and 60 years of age) of 1000 patients each. Figure 1. Disease states in a Markov model describing the natural history of chronic hepatitis C. The rate at which simulated patients moved from one state to another was obtained by critically reviewing the literature. The reported rate of progression from chronic hepatitis C to cirrhosis varies from 1.1% to 10.8% [10-18]. We assumed that patients with chronic hepatitis C may be divided into two groups according to their rate of progression (Table 1). Patients in the indolent disease group would progress from chronic hepatitis to cirrhosis at the lower end of the range (1% per year) reported in the literature. In contrast, chronic hepatitis C in patients in the aggressive disease group would progress to cirrhosis at the higher end of the reported range (10% per year). The rates of progression from compensated to decompensated cirrhosis, from cirrhosis to hepatocellular carcinoma, and from decompensated cirrhosis to death were also obtained from the literature (Appendix Table) [19-24]. We assumed that once cirrhosis developed, the rate of occurrence of complications (that is, hepatic decompensation, hepatocellular carcinoma, and liver-related death) was the same in the indolent and aggressive disease groups. Age-related mortality rates from all causes were based on the 1990 U.S. Vital Statistics [25]. Table 1. Subgroups of Patients with Chronic Hepatitis C according to Virulence of Infection: Estimates Used in the Base-Case Scenario Appendix Table. Estimates Used in the Base-Case Scenario of the Markov Model Interferon- Treatment We simulated a randomized trial that compared the three study groups (no treatment, 6 months of interferon- treatment, and 12 months of interferon- treatment) in each of the four cohorts. Patients in the two treatment groups received 3 million U of interferon- three times a week by self-injection and were monitored every 3 months by clinical examination and laboratory tests. Interferon- therapy was discontinued at 12 weeks in patients in whom aminotransferase levels did not return to normal. Sustained response to treatment was defined as complete and continued disappearance of symptoms and normal liver biochemistry 6 months after discontinuation of treatment. Sustained biochemical response would be accompanied by histologic remission and disappearance of viral RNA from the blood. We assumed that patients who achieved sustained remission would follow the mortality pattern of the general population (cure state in the Markov model [Figure 1]). Patients who did not respond, had relapse, or were not treated would follow the clinical course prescribed by the natural history model. With regard to the proportion of sustained response, we applied different response rates to the indolent and aggressive disease groups (Table 1). Many studies have shown that the factors associated with a more aggressive clinical course of chronic hepatitis C are also predictive of worse response to interferon- treatment [5, 26-28]. For example, multivariate analyses have shown that patients with HCV genotype 1b or high virus levels were up to 10 times less likely to have a sustained response to interferon- therapy than were patients with other genotypes or low virus levels [28]. This association must be considered in the analysis of cost-effectiveness of interferon- because the cost-effectiveness of the drug will otherwise be overestimated. Patients who attain a sustained response to interferon- may be those who would not have had progressive disease without treatment. Conversely, patients who are more likely to die of long-term complications of HCV infection are those who are less likely to respond to interferon- [7]. Costs The costs of treating decompensated cirrhosis and hepatocellular carcinoma were based on a report from the National Institute of Diabetes and Digestive and Kidney Diseases after adjustment for inflation [29]. Costs of liver transplantation were also obtained from the literature and supplemented with institutional data [30, 31]. The cost of interferon- was the average wholesale price plus 20% for costs of injection supplies, clinical and biochemical monitoring, and treatment of side effects from interferon- [32]. These cost estimates are summarized in the Appendix Table. Monetary figures were discounted at an annual rate of 3%. Assessment of Outcome and Sensitivity Analysis Our main outcome measures were the number of deaths from liver disease and total costs. A third outcome, the effect on quality of life over time, was assessed as cumulative quality-adjusted life-years (QALYs) [33]. In computing QALYs, a panel of hepatologists and a nurse specialist used a generic instrument to estimate the utility weight for each disease state [34]. For example, we assigned a utility weight of 0.5 to decompensated cirrhosis, estimating that 1 year of life in a person with decompensated cirrhosis would be equivalent to 0.5 years of healthy life. The other utility weights assigned were 0.95 for chronic hepatitis, 0.8 for compensated cirrhosis, 0.8 for the time after liver transplantation, 0.25 for hepatocellular carcinoma, and 0 for death. We discounted the benefits of interferon- treatment (QALYs) at the same rate used for discounting costs (3%). Incremental cost-effectiveness was assessed by computing cost per QALY gained; the three strategies were compared in a pairwise fashion. Sensitivity analyses were performed by varying the value of the variables used in the model to identify those that had the greatest effect on the conclusions. Variables associated with a more than twofold change in cost-effectiveness in this process were considered influential and are presented in the Results section. All cost figures were rounded to the nearest

Hepatic cyst infection in autosomal dominant polycystic kidney disease

100. Results Natural History Model of Chronic Hepatitis C Figure 2 shows the results of the Markov model that describes the progression of liver disease in the cohort of a representative age group (40 years of age). At time zero, all patients have chronic hepatitis C. During the ensuing years, an increasing proportion of patients moves throug

Relationship between hepatitis C genotype and severity of recurrent hepatitis C after liver transplantation

To characterize the syndrome of hepatic cyst infection in autosomal dominant polycystic kidney disease (ADPKD) and to review its diagnosis and management, we retrospectively studied five such cases in patients from our institution and nine detailed case reports from the literature. The clinical manifestations were an acute (58%) or subacute (42%) febrile illness, typically associated with tenderness in the right upper quadrant, leukocytosis, a very high erythrocyte sedimentation rate, but minor abnormalities of liver function tests. Bacteremia was present in 7 of 11 patients. Enterobacteriaceae grew in pure culture from the cyst fluid in 9 of 12 patients. Complex cysts were observed by ultrasonography (in four of eight patients), computed tomography (in six of nine), and magnetic resonance imaging (in two of two). 111In leukocyte scans were positive in all four patients in whom they were done, and 67Ga scans were positive in only one of three patients. An unfavorable outcome was observed in six of seven patients treated with only antibiotics, in contrast with one of seven patients who received antibiotics and early drainage. In two patients, ciprofloxacin cyst levels were 2.3 and 4.8 times higher than the level in serum; in a third patient, cyst levels remained in therapeutic range 30 hours after the last dose of ciprofloxacin, at which time serum levels were undetectable. Clinical and laboratory features and the use of modern scanning techniques facilitate a prompt diagnosis of infection in hepatic cysts in ADPKD. The treatment of choice is a combination of percutaneous drainage and antimicrobial therapy.

Acquired hypocupremia after gastric surgery

BACKGROUND Recurrence of hepatitis C virus (HCV) infection after liver transplantation is universal, but the relationship between hepatitis C genotype and posttransplant outcome has been controversial. The aim of this study was to assess the relationship between hepatitis C genotype on posttransplant frequency of recurrent hepatitis, histologic severity of recurrence, and progression to cirrhosis. METHODS We studied 42 HCV RNA positive patients who received transplants between 1985 and 1994. Sera were tested for HCV RNA and protocol liver biopsies were in obtained the posttransplant period. Biopsies were scored according to the histologic activity index (HAI) and staged in a blinded fashion. RESULTS The distribution of hepatitis C genotypes distribution was as follows: 1a, 19 (45%); 1b, 17 (40%); 2b, 3 (7%); and 1 each of 2a, 3a, and 4a. There was histologic evidence of hepatitis in 38 of 42 (90.4%) of patients. Hepatitis C was mild, moderate, or severe (HAI>3) in 38% of grafts and minimal (HAI 0-3) in 62%. Overall HAI scores and histologic stage were higher in the genotype 1b group. Six of 17 (35%) genotype 1b patients had cirrhosis compared with 2 of 25 (8%) in the non-1b genotype group. CONCLUSIONS (1) Histologic evidence of recurrent hepatitis C is seen in 90% of liver allografts; (2) Histologic hepatitis C recurs with similar frequency in genotype 1b and non-1b recipients; (3) Genotype 1b is associated with more severe histologic disease recurrence than non-1b genotypes; (4) Genotype 1b appears to be associated with a higher degree of posttransplant fibrosis and cirrhosis than non-1b genotypes.

Herpes esophagitis: clinical syndrome, endoscopic appearance, and diagnosis in 23 patients

BACKGROUND & AIMS Copper absorption in humans probably occurs in the stomach and duodenum. Copper is essential for the structure and function of the nervous system and acquired copper deficiency in humans has been recognized to cause a myelopathy that resembles vitamin B12 deficiency. Acquired copper deficiency is not a well-recognized complication of gastric surgery. In Menkes disease a defect in enterocyte transport of absorbed copper results in increased copper content in the duodenal mucosa and hypocupremia. METHODS We report 2 patients who developed neurologic deficits with copper deficiency many years after gastric surgery. In 2 other patients with hypocupremic myelopathy but no history of gastric surgery, colonic copper was measured to determine if an absorptive defect similar to that seen in Menkes disease may be responsible for hypocupremia. RESULTS In all 4 patients copper deficiency was identified as the cause of the myelopathy. In 2 patients the copper deficiency occurred after gastric surgery. Eight additional patients with copper deficiency after gastric surgery were identified from the literature. Six of these 8 patients also had neurologic manifestations. Colonic mucosa copper content was increased in the 2 patients with hypocupremia without prior gastric surgery. CONCLUSIONS Acquired copper deficiency may be a delayed complication of gastric surgery and may result in a myelopathy similar to that seen with vitamin B12 deficiency. In some patients with acquired copper deficiency no cause for the hypocupremia may be evident and a primary absorptive defect should be considered.

Myelopathy due to copper deficiency

The unexpected diagnosis of herpetic esophagitis in a patient with nausea led us to review our experience with this disease. Review of our records from 1979 to 1989 produced 23 cases proven by endoscopic culture or microscopic examination (Cowdry-type A inclusions), the largest such series reported to date. Twenty-two of the 23 patients were immunocompromised. Odynophagia and chest pain were each present in half of the cases, but 26% of patients had neither. Gastrointestinal bleeding was attributable to herpetic esophagitis in 30%. Thirty percent of patients had disseminated herpes simplex infection and 70% had simultaneous infections with other organisms. Endoscopic findings included nonspecific inflammation, discrete ulcers, coalescent ulcers, and pseudomembranous esophagitis. Herpes virus was not suspected endoscopically as the cause of esophagitis in 30% of cases. Culture was slightly more sensitive than microscopic examination for diagnosis (89% vs. 76%), but both methods should be employed in any immunocompromised patient with esophagitis.

A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis.

Copper is an essential trace metal and plays key roles in the structure and function of the nervous system, vascular, and skeletal tissues and in hematopoiesis and catecholamine metabolism. Inherited copper deficiency (Menkes’ disease) results in intellectual deterioration, failure to thrive, seizures, abnormal hair, and connective tissue abnormalities. Due to the ubiquitous distribution of copper and the low daily requirement, acquired copper deficiency is extremely rare in humans. Ataxic myelopathy due to copper deficiency does occur in ruminants and is called swayback.1 The hematologic manifestations of acquired copper deficiency are well described,2 but the neurologic manifestations of acquired copper deficiency in humans are not widely appreciated. We describe a case of myelopathy that occurred in the setting of copper deficiency. A 65-year-old man was evaluated for a 5-year history of progressive gait difficulty. For 1 year prior to evaluation, he had been using a cane and had paresthesias involving the feet and hands. He had been taking 200 to 400 mg of zinc a day for cold prevention for 22 years (recommended daily allowance of zinc, 15 mg/day). Neurologic examination …

Abnormalities in tests of copper metabolism in primary sclerosing cholangitis

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once‐daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300‐2000 ng/mL, transferrin saturation ≥45%, and no known history of cirrhosis were enrolled in this dose‐escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty‐nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose‐dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48‐week treatment period; six patients had alanine aminotransferase >3× baseline and greater than the upper limit of normal range, and eight patients had serum creatinine >33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to <250 ng/mL. Conclusion: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population. (HEPATOLOGY 2010)