Resolution of alcoholic neuropathy following liver transplantation
Article first published online: 19 NOV 2004
Copyright © 2004 American Association for the Study of Liver Diseases
Volume 10, Issue 12, pages 1545–1548, December 2004
How to Cite
Gane, E., Bergman, R. and Hutchinson, D. (2004), Resolution of alcoholic neuropathy following liver transplantation. Liver Transpl, 10: 1545–1548. doi: 10.1002/lt.20282
- Issue published online: 19 NOV 2004
- Article first published online: 19 NOV 2004
Between 10 and 20% of adult liver transplants are performed for end-stage alcoholic liver disease. Severe extrahepatic end-organ damage from alcoholism (cardiomyopathy, pancreatitis, central nervous system injury, and neuropathy) is widely regarded as an absolute contraindication to liver transplantation, despite a lack of data on the effect of transplantation on these complications. We describe such a patient who presented with decompensated alcoholic liver disease and moderately severe peripheral neuropathy. Both his liver failure and neuropathy progressed despite 9 months abstinence and intensive nutritional support. By 12 months post-transplant, however, this patient had regained almost normal muscle strength, with associated recovery in sensory and motor conduction velocities. Direct alcohol toxicity, nutritional and vitamin deficiencies, and liver failure were all likely etiologic factors in this patient's neuropathy. In conclusion, this case suggests that peripheral neuropathy in a patient with alcoholic cirrhosis may resolve following liver transplantation and should not constitute a contraindication to transplantation, even when it is disabling. (Liver Transpl 2004;10:1545–1548.)
Alcoholism produces dose-related injury to the peripheral nervous system. Important modifying factors include the presence or absence of protein-calorie malnutrition, vitamin deficiency, and associated liver disease. Peripheral neuropathy is also found in the majority of patients with cirrhosis, irrespective of etiology.1 However, in non-alcoholic patients it is usually mild and asymptomatic.2
Severe, extrahepatic end-organ damage is generally considered a contraindication to orthotopic liver transplantation (OLT) for alcoholic liver disease, despite the paucity of literature on the prognosis of extrahepatic disease after OLT. We were recently referred for transplant evaluation a patient with progressive severe liver impairment due to decompensated alcoholic cirrhosis and a disabling peripheral neuropathy. Orthotopic liver transplantation was followed by dramatic clinical and electrophysiologic improvement of his neuropathy. We review the relevant literature and discuss the effects of OLT on peripheral neuropathy.
In February 1999, a 50-year-old linesman was admitted to the hospital in another city with a 2-month history of progressive weakness of both legs. On the day of admission he had been unable to climb the ladder out of a manhole. He admitted a 20-year history of drinking more than 100 g of alcohol per day. On examination, he was jaundiced with bilateral parotid hypertrophy and multiple spider nevi. His spleen was tippable but liver not palpable with reduced span to percussion. Blood tests revealed serum bilirubin 68 μmol/L (normal 2–20), albumin 31 g/L (normal 33–47), and International Normalized Ratio (INR) 1.9 (normal .8–1.2). Ultrasound demonstrated a small heterogeneous liver consistent with cirrhosis, an enlarged spleen, and a moderate amount of ascites. Investigations for other etiologies of chronic liver disease were negative (hepatitis virus serology, autoimmune serology, α1-antitrypsin level and phenotype, iron and copper studies).
He deteriorated steadily over the next 9 months despite abstinence from alcohol, thiamine supplementation 50 mg daily, a low-salt diet, and nutritional supplementation (2 cans of Ensure Plus each day equivalent to 710 calories, in addition to high-calorie, high-protein diet aiming for total daily caloric input of 2500 calories). He required repeated admissions to hospital for large volume paracentesis for diuretic-resistant ascites. His liver synthetic function continued to deteriorate; in October 1999 bilirubin was 429 μmol/L, albumin 27 g/L, and INR 2.2.
In November 1999 he was referred to the New Zealand Liver Transplant Unit for evaluation for elective liver transplantation. Despite 9 months abstinence from alcohol, his Child's-Pugh score had risen to 13 and a Model for End-stage Liver Disease (MELD) score was 28. Detailed nutritional assessment including body composition analysis revealed significant proteincalorie malnutrition (body mass index [BMI] = 27; total body protein 73% predicted) and overhydration (total body water 51 L = 77% fat-free mass). Cardiac assessment, including ECG and echocardiography, was normal.
On neurologic evaluation he reported that his leg weakness had not improved with abstinence. He could not rise from a chair without use of his arms, and he had considerable difficulty ascending stairs. He denied dysphagia, myalgia, and sensory symptoms. This patient had asthma, for which he had required short-course oral prednisone therapy (40 mg reducing to nil over 7 days) approximately once per annum. There was no other exposure to drugs known to produce peripheral neuropathy or myopathy.
Neurological examination showed symmetric moderate wasting of proximal leg muscles and moderate (Medical Research Council grade 3) generalized weakness of each leg, mildly greater proximally. There was mild (Medical Research Council grade 4) diffuse weakness of both arms with sparing of the finger flexors. The knee and ankle reflexes were absent bilaterally, and the triceps reflexes were hypoactive. Sensory examination showed impaired light touch and proprioception in both feet. There was no cerebellar ataxia and no clinical evidence for encephalopathy.
Serum vitamin B12 level was 719 pmol/L (normal range 140–780); red cell folate was greater than 1400 nmol/L (normal range 410–1400). Serum potassium, glucose, creatinine, creatine kinase, and thyroid function tests were all normal. HIV serology was negative. No gammopathy was detected on serum protein electrophoresis. Anti-smooth muscle antibodies were present in low titer (1:80); antinuclear and other autoantibodies were negative.
Nerve conduction studies of the right median, peroneal, and sural nerves showed absent sural responses; reduced amplitude peroneal compound muscle action potentials (1.0 mV; normal > 2.0); increased right median F wave latency (36.9 ms; normal < 32); and slowing of motor and sensory conduction velocities (Table 1). Needle electromyography showed increased motor unit size, reduced motor unit recruitment, and polyphasia. These findings indicated a chronic sensorimotor peripheral neuropathy.
|Right Median||Right Peroneal Motor|
Muscle biopsy from vastus lateralis showed abundant atrophic muscle fibers, histochemically either type 1 or type 2, occurring singly or in groups with up to six fibers per group. Scattered fibers were highly atrophic. There was additional mild type 2B fiber atrophy. There was no fiber type grouping. The appearances indicated denervation atrophy without reinnervation. The combined clinical, biochemical, electrophysiological, and histological features established that his limb weakness was due to peripheral neuropathy. A likely explanation for the mild type 2B fiber atrophy was muscle disuse.
Despite uncertainty about the prognosis of his peripheral neuropathy, he was accepted for liver transplantation. He continued to deteriorate while on the waiting list. He became encephalopathic for the first time following an episode of spontaneous bacterial peritonitis. He received a whole cadaveric liver transplant in December 1999, followed by standard dual immunosuppression (tacrolimus, target trough levels 10–15 μg/L for the first 3 months and 5–10 μg/L thereafter; prednisone 20 mg/day for 2 weeks, reducing by 2.5 mg every two weeks until withdrawn). His postoperative course was unremarkable and nutritional supplements were withdrawn at 8 weeks after transplantation.
Following the transplant he noticed progressive recovery of strength in both legs. After 2 months he was able to walk unaided, and after 6 months he was able to rise from a chair without difficulty and to negotiate stairs normally. He subsequently returned to full employment. Repeat neurological examination 12 months post-transplant showed significant improvement in motor function. Bilateral quadriceps wasting persisted, but power was now normal except for mild bilateral weakness of intrinsic hand muscles, the finger extensors, and great toe dorsiflexion. The ankle reflexes were now present with reinforcement. The sensory alterations were unchanged from one year earlier.
Repeat nerve conduction studies performed 5 and 11 months after OLT (see Table 1) showed progressive recovery of peripheral nerve function. Corresponding BMIs at these two time points were 31.5 and 34.0. His BMI fell to 30 following institution of a regular exercise program.
This report describes the dramatic improvement of muscle strength following liver transplantation in a patient with decompensated alcoholic cirrhosis. The preoperative work-up included nerve conduction studies and muscle biopsy, establishing clearly that peripheral neuropathy was the basis for his weakness. Direct cumulative neurotoxicity from alcohol, nutritional and vitamin deficiencies associated with alcoholism, and liver cirrhosis each probably contributed to his neuropathy.
Alcoholic neuropathy is initially asymptomatic. With continued drinking over years, patients slowly develop distal paresthesia and burning followed by numbness, weakness, areflexia, and sensory ataxia. Axonal degeneration is the predominant pathological change.3 Attempts have been made to separate the influence of alcohol from that of malnutrition, but the results have been conflicting.3, 4 In patients without liver failure, slow clinical and electrophysiological recovery occurs with alcohol abstinence, which is usually also associated with improved food intake and nutritional status.5
Liver cirrhosis is an independent cause of peripheral neuropathy. In a recent report, 58 patients with chronic liver disease from a variety of causes were evaluated for neuropathy using neurological examination, nerve conduction studies, and quantitative sensory and autonomic function tests.2 Overall, 41 (71%) of the patients had clinical or laboratory evidence for peripheral neuropathy. In the majority of patients, this was subclinical or accompanied by minor symptoms. The nerve conduction studies suggested that the pathological change was axonal degeneration. Both the incidence of peripheral neuropathy (83%) and its severity were higher in the 12 patients with alcoholic liver disease, although neither of these differences reached statistical significance. We believe that liver failure made an important contribution to the peripheral neuropathy in our patient. First, despite a 20-year history of alcohol excess, his liver failure and the neuropathy became symptomatic in parallel. Second, his neuropathy failed to improve preoperatively, despite 9 months of abstinence and nutritional supplementation, measures expected to improve a purely alcoholic neuropathy. Finally, his neuropathy improved dramatically following successful liver transplantation.
A single previous paper has described improvement of peripheral neuropathy after OLT in a patient with alcoholism and liver failure. Spahn et al. reported a 55-year-old woman with decompensated alcoholic cirrhosis and muscle wasting whose neuromuscular function improved after OLT.6 However, the bed-bound status of this patient in the pretransplant phase was attributed to liver disease, and her impaired neuromuscular function was neither quantified nor investigated preoperatively. Postoperative evaluation was hindered by the presence of encephalopathy and severe ataxia. Nerve conduction studies were not performed until 27 months after OLT, at which time the tibial conduction velocity remained an unusually low 16.8 m/s.
Others have described improvement of peripheral neuropathy after OLT in non-alcoholic patients. Where stated, the peripheral neuropathy in these patients has been mild or asymptomatic. McDougall et al. reported a 40-year-old teetotal man with end-stage hepatitis B cirrhosis and a mild peripheral neuropathy.7 Examination prior to OLT showed normal strength, absent knee and ankle reflexes, and mild distal sensory loss in the legs. Nerve conduction studies showed slowing of motor and sensory conduction velocities in both legs. Nine months after OLT, he had regained the reflexes in his legs, and the sensory alterations were less marked. Repeat nerve conduction studies showed recovery of conduction velocities into the normal range.
Höckerstedt et al. performed neurological examinations and nerve conduction studies in 8 non-alcoholic patients before and after OLT.8 All patients had a reduced muscle strength score preoperatively, but few details of the derivation of this score were given. Only two patients had clinical signs of peripheral neuropathy. Strength returned to normal in all patients after OLT. Nerve conduction velocities repeated 6–12 months after OLT showed modest, non-significant improvement.
Finally, Lee et al. performed nerve conduction studies in 25 patients with end-stage liver disease before and 6 months after OLT.9 The causes of the liver failure and the results of neurological examination were not given. Preoperatively, 13 (52%) of the patients had at least one nerve conduction abnormality. All patients showed electrophysiological improvement after OLT.
Advanced, irreversible non-hepatic disease—such as cardiomyopathy from hemachromatosis, or Korsakov psychosis due to alcoholism—is an important contraindication to liver transplantation. We initially considered the peripheral neuropathy in our patient to be a contraindication to OLT due to its significant impact on his quality of life and the uncertainty about its prognosis following transplantation. Our experience with this patient suggests that peripheral neuropathy in a patient with alcoholic cirrhosis is reversible and should not constitute a contraindication to OLT, even when the neuropathy is disabling.