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The following peripheral neuropathy-associated systemic diseases (PNASDs) are discussed:

  1. Hepatic disorders
  2. Endocrinopathies
  3. Critical illness
  4. Sarcoidosis
  5. Amyloidosis
  6. Celiac disease


PNASD occurs when nerve fiber repair mechanisms are unable to keep up with accumulation of damage.

Epidemiology including risk factors and primary prevention

PNASD Epidemiology of Polyneuropathy (PN) Other Information
Liver disease Hepatitis C: Incidence around 5%-10% develop PN or mononeuritis multiplex. Epidemiology undefined. Causal relationship questioned.
Thyroid disease1-3 Hypothyroidism: Highly variable between studies. About 50% incidence. Hyperthyroidism: about 25% of severe thyrotoxicotics. Most PN in hypothyroidism is subclinical with electromygraphic findings only.
Critical illness4 70% of patients in intesive care unit for ≤2 weeks. Seen with severe inflammatory response syndrome (SIRS), sepsis, multiorgan failure; associated with increased mortality and length of weaning from the ventilator.
Amyloidosis2,5 About 15%-30% of patients. Presenting feature in 10-%20%. Symptoms usually present 1 year prior to diagnosis.
Sarcoidosis2,5 Prevalence: 1-64 in 100,000. Onset mostly around 20-29 years of age, usually before 40 years old. Scandinavian and Japanese women with second peak incidence when >50 years old. Prevalance African-American >> Caucasians. 5% with both peripheral nervous system and central nervous system involvement.
Celiac disease2,5 6%-12% prevalance. Celiac disease prevalence about 1% in American and Europeans. Considerable number of undiagnosed patients possible.


Cirrhosis-associated PN is likely from cirrhosis itself, not the specific cause of cirrhosis. A 2003 study by Kharbanda et al failed to show statistically significant deference in neuropathy incidence between patients with alcohol and non-alcohol cirrhosis.15 Pathogenesis unknown in PN is associated with noninfectious liver disease.6Hepatitis B and C cause vasculitic PN from immune complex deposition into vasculature, activating monocytes to release proinflammatory cytokines. This in turn attracts neutrophils, which release free radicals that ultimately cause nerve damage. Increased messenger ribonucleic acid expression in hepatitis C suggests involvement of cytotoxic T-cells.2

Hypothyroidism PN is not completely understood. Etiologies include the following: increased compartmental pressure from mucinous infiltration of the perineurium and endoneurium leading to focal demyelination and compression, disruption of microtubule assembly causing axonal degeneration, and secondary demyelination.7,8

Critical illness PN (CIP) is not completely understood; it involves multiple pathways (metabolic, inflammatory, bioenergetic alterations). Possible mechanisms include the following: microvascular changes in peripheral nervous system (PNS) (increased E-selectin expression), altered lipid serum profile, damage or inhibition of complex I of the respiratory chain causing muscle adenosine triphosphate depletion, and bioenergetic failure.9

Amyloid PN is caused by insoluble beta-fibrillar protein deposition in nerve sheaths, perineuronal tissues, and neural vasculature. Ischemic, infiltrative, inflammatory, and toxic metabolic factors are also implicated causing axon and neural capillary compression leading to loss of myelin fibers and axonal degeneration. Loss of unmyelinated fibers is also observed.

Sarcoidosis PN is caused by cell-mediated immune response with nerve granulomas and multinucleated giant cell (MNGC) formation. Memory T-cells recruit and activate macrophages, which fuse into MNGCs and gain secretory capabilities and release proteolytic enzymes damaging neighboring cells. Epineurium-located granulomas cause little to no damage. Serious damage occurs with granuloma-related necrotizing vasculitis, when endoneurium inflammation causes ischemic nerve lesions and axonal degeneration.

Celiac disease pathogenesis is uncertain (malabsorption vs other immunologic mechanisms). Malabsorption includes vitamins B12, B6, and E and metals, especially copper. Autoimmune diseases predispose the patient to more autoimmune diseases, and the PN in celiac patients may be a manifestation of these other autoimmune diseases. Similarity between antigens targeted by the immune system and proteins expressed in the PNS (molecular mimicry) is a possibility.2,5

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Symptoms generally present with paresthesias in the feet in the early stage with progression in a classic stocking-glove distribution. Hand involvement usually begins once sensory loss progresses to the mid-calf or knee. Weakness follows the same pattern of progression and patient complaints, including foot drop and hand intrinsic weakness. Autonomic symptoms include the following: gastroparesis, erectile dysfunction, and orthostatic hypotension.

Liver Disease

  1. Chronic hepatic: the majority are subclinical, with a distal symmetric pattern, sensory > motor, large-fiber (paresthesia, numbness) axonal PN.
  2. Infectious hepatic: mononeuritis multiplex pattern is most common.2


  1. Hypothyroid-associated PN presents similarly to diabetic polyneuropathy as a distal symmetric, large fiber sensory polyneuropathy. It is often asymptomatic. Woltman sign is a delayed relaxation phase on muscle stretch reflexes (MSRs) seen with clinically overt hypothyroidism and has a 72% positive predictive value.3
  2. Hyperthyroid-associated neuropathy commonly presents clinically as a distal symmetric sensory axonal PN.10

Critical Illness

  1. Seen in neurosurgical, multitrauma, burns, and after major vascular repair (aortic abdominal aneurysm, coronary artery bypass graft). Suspicion should be raised in a patient with limb weakness, loss of MSRs, or unable weaning off ventilation post-SIRS. Cranial nerve (CN) involvement suggests Guillain-Barre Syndrome (GBS), motor neuron disease, or critical illness myopathy. Difficulty evaluating sensation is common from encephalopathy or sedation. In the setting of absent nail bed pressure response, supraorbital pressure grimace suggests intact pain sensation


  1. The presentation of primary amyloidosis is quite variable: frequently, slowly progressive, distal symmetric mixed-fiber, sensorimotor PN with or without autonomic involvement (orthostatic hypotension, diarrhea, bladder dysfunction, impotence). Carpal tunnel syndrome (CTS) present in 25% from wrist flexor retinaculum amyloid deposition. Small-fiber findings (pain, temperature) and CTS mandate amyloidosis workup. Constitutional symptoms (weight loss, organ involvement) should raise suspicion of primary amyloidosis. A Mayo Clinic study demonstrated a median survival of 13.2 months following diagnosis, with 7% surviving after 5 years. Systemic symptoms at presentation is a poor prognosticator. Median survival if congestive heart failure is seen at presentation is 4 months.
  2. Hereditary amyloidosis consists of 4 syndromes with slightly varying characteristics from primary amyloidosis.


  1. Predominantly involves cranial nerves: multiple fluctuating and remitting CN palsies, CNs successively and randomly involved over weeks or months. Up to 50% with facial nerve palsy. Ocular involvement in about 25%. Hearing loss, vertigo, and tinnitus also reported. Outside of the CN, PN with granulomas is extremely uncommon; observed PN covers a wide spectrum of presentations (focal and multifocal sensorimotor neuropathy, GBS, multifocal subacute or chronic sensorimotor neuropathy, chronic symmetric sensory PN, subacute multifocal sensorimotor neuropathy with conduction block).2,5Hoever, small fiber neuropathy is fairly common.19

Celiac PN

  1. Progressive course correlates with disease severity and duration. Can present as a non-length-dependent neuropathy (ganglionopathy) or exclusively small-fiber neuropathy.

Specific secondary or associated conditions and complications

Complications include ulcers, claw-toe deformity, Charcot joint, and amputation.11

GBS may occur at the onset of infectious hepatitis.2



Obtaining history of distribution and onset of symptoms, associated medical conditions, and family history helps guide making the diagnosis.

Physical examination

PNASD generally presents as a distal symmetric sensory neuropathy. Depending on etiology, symptoms may be indicative of dysfunction of small fibers (pain, temperature, light touch), large fibers (vibration, proprioception, light touch), or both. Motor involvement occurs in late disease leading to atrophy and weakness of intrinsic foot and hand muscles.

Functional assessment

Careful assessment of home and community function remains important. Special attention should be paid to mobility and fall prevention, especially at night time because of sensorimotor and proprioception loss. Home modifications (e.g., clearing clutter and throw rugs, automated lights, grab bars) can help reduce fall risk. Impairments can be accommodated with ankle-foot orthoses and assistive devices as appropriate.

Laboratory studies

Laboratory evaluation of peripheral neuropathy should begin with the following:

  1. Comprehensive metabolic profile
  2. Fasting blood glucose
  3. Vitamin B12 and possible metabolites (homocysteine, methylmalonic acid)
  4. Thyroid-stimulating hormone
  5. Serum and urine immunofixation

Supplemental assessment tools

Electrodiagnostic (EDx) tools are necessary for atypical presentations (e.g., asymmetry of signs or symptoms, weakness > sensory loss at initial presentation, proximal signs or symptoms > distal, rapidly progressive disease course).12Chronic inflammatory demyelinating NP must also be in the differential because improvement may occur with proper treatment.13

Edx Findings
PNASD Sensory Nerve Action Potential Compound Muscle Action Potential Con-duction Velocity Latency Electro-myography Other
Chronic hepatic Reduced Reduced Minimally reduced (sural and peroneal affected first) About 50% with autonomic NCS abnormalities.
Infectious hepatic Asymmetry Reduced Increased spontaneous activity
Hypo-thyroidism Reduced or absent Mild slowing of motor and sensory Pro-longed distal motor Combined axonal and demye-linating
CIP Normative, reduced, or absent Reduced or Absent. Amplitude ratio of <0.5 of motor nerve todirect muscle stimulation. Normative Fibrillations CIP electrodiagnosis is criterion standard for diagnoses
Sarcoidosis Widely variable presentations. Generally sensorimotor. In case of multifocal motor and sensory neuropathy, motor conduction blocks and decreased nerve conduction velocity are observed.

Nerve biopsies can provide important information for diagnosis in suspected vasculitis, amyloidosis, and rarely autoimmune demyelinating diseases but are not routinely indicated because of their invasiveness.14

  1. No firm guidelines on when to biopsy in CIP, but it may be warranted in patients with atypical presentations, previous immunosuppression (cytomegalovirus, myositis, polymyositis, direct muscle infections, other conditions mimicking CIP), or when additional prognostic information may help plan the future level of care.
  2. Nerve biopsies in primary biliary cirrhosis are unique, with lipid laden cells found within the nerve fasicles.2

Magnetic Resonance Neurography (MRN) provides a direct and non-invasive look at peripheral nerve injuries. There are limited studies on the use of MRN to detect PNASDs, but it has been studies in patients with transthyretin familial amyloid polyneuropathy, and was able to detect early nerve lesions in asymptomatic TTR gene carriers. This may allow for earlier diagnosis of the disease. 19

Social role and social support system

Consequences of PN can be life changing, with worst case scenarios involving limb amputations and functional deficits.


Available or current treatment guidelines

Generally, progression of PNASDs improve or halt with treatment of underlying disease.

There is no specific treatment for liver disease-associated neuropathy. Post-transplant effects on neuropathy have not been studied. Corticosteroids, cytotoxic immune suppression, and plasmapheresis have been reported in case studies and have some effect on hepatitis C neuropathy.2 Two randomized clinical trials showed rituximab was superior to placebo and conventional treatments including steroids, plasmapheresis and cyclophosphamide in treating hepatitis C neuropathy.  However, a 2014 Cochrane Review found there was insufficient evidence to guide HCV neuropathy treatment decisions with the use of rituximab, antiviral treatment or interferon alfa. 16

No specific treatment arrests or reverses CIP, but it may improve if sepsis or multiorgan failure resolves. Supportive therapy to weather the complications associated with SIRS is most important. Strict insulin control (80-100 mg/dL) reduces incidence of CIP by 44% and overall mortality. Insulin is a neurotrophic factor, hypothesized to be neural protective during SIRS, and facilitates regeneration.2

In primary amyloidosis, despite treatment of the overall condition and prolonged survival, symptoms of peripheral neuropathy do not improve.

In familial amyloid PN with transthyretin mutation, liver transplantation has shown to benefit. Jonsen et al showed 10 of 12 patients reported an improved quality of life following transplant. Adams et al showed that motor nerve involvement stabilized in 7 of 11 patients with mild sensory motor neuropathy and in 2 of 8 with severe sensory motor neuropathy. Tafamadis may delay progression of peripheral neuropathy impairments in patients with familial amyloid PN.17

Prednisone, initially at 1 mg/kg/d, is used to treat neurosarcoidosis. In resistant cases, immunosuppressive treatment with methotrexate, cyclosporine, and azathioprine has been used. PN improves with treatment in most cases.2,5 Small fiber neuropathy symptoms may improve with intravenous immune globulin or anti-tumor necrosis factor α.18

In celiac disease, a gluten-free diet must be started whether or not PN is associated with the disease. It is unclear if a gluten-free diet has an effect on PN. In 2006, Hadjivassiliou et al performed a systematic, controlled study of the effect of a gluten-free diet on 35 patients with celiac disease-associated neuropathy, with close serologic monitoring of adherence to the gluten-free diet. They found significant improvement in the treated group compared with the control group after 1 year on the diet. Vitamin and mineral supplementation may have some benefit. The use of immunomodulatory treatments, immunoglobulin infusions, or immunosuppressants for celiac disease-associated neuropathy remains controversial.2,5

Coordination of care

Coordinating care between the physiatrist, primary care physician, neurologist, endocrinologists, internists, rheumatologists, gastroenterologists, pulmonary subspecialists, physical therapist, occupational therapist, dietician, podiatrist, and orthotist is imperative.

Patient & family education

Education on careful skin care of feet is important. Fall prevention strategies should be reviewed. Education to treat the underlying problem is important and may include diet and exercise education.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Treatment for neuropathies associated with systemic diseases is usually treatment of the underlying disease.

Care should be exercised when treating neuropathic pain in patients with liver disease. Reduced hepatic metabolism results in increased adverse effects.

Frequent weight shifting is mandatory for patients in the intensive care unit to prevent decubitus ulcers.


Cutting edge concepts and practice

Addition of magnetic resonance neurography (MRN) as a useful diagnostic test will depend on its availability, cost efficiency, and utility.


Gaps in the evidence-based knowledge

The effects of post-liver transplantation on chronic liver neuropathy have not been studied.

Imaging protocols and PNASD findings for MRN needs to be studied.


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  2. Donofrio, Peter D.Textbook of Perhipheral Neuropathies. New York (NY): Demos Medical; 2012.
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Original Version of the Topic

Christopher T. Plastaras, MD, Jerry Fang, MD, William Gleason, MD. Peripheral Neuropathies Associated with Systemic Disease. 09/20/2014.

Author Disclosure

Sarah E Clevenger, MD
Nothing to Disclose

Stephen Kishner, MD
Nothing to Disclose