global health case - nephrotic syndrome

Dr. Kaitlin Brooke presented an interesting global health case from her rotation in Botswana. The case was a middle age female who presented with subacute bilateral lower extremity edema and generalized weakness, who was found to have anasarca on exam with work up including labs and CXR concerning for nephrotic syndrome presumed secondary to secondary amyloidosis from chronic pulmonary TB. She was empirically treated for tuberculosis and received steroids for her nephrotic syndrome. Dr. Brooke shared many interesting facts about practicing medicine in a resource limited setting like Botswana!

Learning Points:

We discussed the differential diagnosis of lower extremity edema by primary mechanism including:

  • Increased plasma volume due to renal sodium retention (heart failure, nephrotic syndrome, drugs, pregnancy, etc.)
  • Venous obstruction or insufficiency (cirrhosis or hepatic venous obstruction, acute pulmonary edema, local venous obstruction, etc.)
  • Hypoalbuminemia (protein loss through nephrotic syndrome or protein-losing enteropathy or reduced albumin synthesis through liver disease or malnutrition)
  • Increased capillary permeability (burns, trauma, inflammation or sepsis, allergic reactions, ARDS, diabetes, etc.)

Nephrotic syndrome is defined as proteinuria >3.5 g/d, hypoalbuminemia < 3.5 mg/dL, edema, and increased cholesterol. Etiology can be primary glomerular disease (FSGS, membranous nephropathy, minimal change disease, membranoproliferative GN) or due to systemic diseases (DM2, amyloidosis, SLE, cryoglobulinemia).

Dr. Brooke shared her workup of hypoalbuminemia in a resource limited setting detailed below.

hypoalbuminemia.PNG

Hypercalcemia of Malignancy

Thank you to Dr. Huber for presenting an intersting case where a young male presented with nausea and was found to have hypercalcemia of malignancy from myeloid sarcoma. This brought up several learning points when thinking about the differential for hypercalcemia, the workup and treatments.

Hypercalcemia can be thought of as secondary to:

  • Parathyroid disorders: FHH, adenomas, MEN, primary or tertiary hyperparathyroidism
  • Vitamin D: iatrogenic ingestions, granulomatous disease (TB, sarcoid, etc)
  • Endocrinopathies: adrenal insufficiency, hyperthryoidism, pheochromocytoma, acromegaly
  • Malignancy: leukemia/lymphoma, sarcoma, RCC, osteolytic metastases
  • Medications: thiazides, lithium, vitamin A, theophylline
  • Immobilization
  • Milk-Alkali Syndrome
  • Genetic Disorders: William's syndrome, Murk Jansen syndrome

In working up hypercalcemia, the following is a good approach once hypercalcemia has been confirmed (i.e. correct the calcium for albumin and check an iCal).

Diagnostic approach to hypercalcemia per UpToDate

Diagnostic approach to hypercalcemia per UpToDate

When thinking about treatment consider the following:

  • Fluids (preferably normal saline) to restore intravascular volume and improve calcium excretion (typically 200-300ml/hour UOP)
  • Loop Diuretics (occasionally used to prevent volume overload)
  • Calcitonin inhibits bone resorption via interference with osteoclast function
  • Bisphosphonates inhibit bone resorption via interference with osteoclast function
  • Glucocorticoids decreases intestinal calcium absorption and VitD production for those with granulomatous disease or lymphoma
  • Denosumab inhibis RANKL
  • Calcimemtrics to reduce PTH in parathyroid disease
  • Dialysis

In this case, the patient was diagnoses with myeloid sarcoma on biopsy. This is considered a type of AML where less than 1% of patients present with extramedullary disease either simulataneously or preceding bone marrow involvement. It is also called granulocytic sarcoma, myeloblastoma or chloroma. According to UpToDate, it should be considered in the differential for "small round, blue cell tumors" and if there are eosinophilic myelocytes on biopsy. It is treated like AML.

Myeloid sarcoma on hematoxylin-eosin stain revealing "small blue round cells"

Myeloid sarcoma on hematoxylin-eosin stain revealing "small blue round cells"

Inflammatory myopathy

Thanks Eliot for presenting a great case. This is a case of an elderly gentleman with a history of fibromyalgia, exogenous iodine intake presenting with subacute progressive lower extremity weakness found to have abnormal TFTs and troponemia found to have a biopsy proven idiopathic inflammatory myopathy.

A) H&E of PM. B) H&E of IBM. From NEJM article below.

A) H&E of PM. B) H&E of IBM. From NEJM article below.

Main Points:

  • 1) The approach to weakness can be thought of as CNS, PNS, oxygen delivery and psych. See this blog post for more information.
  • 2) Patients with a new diagnosis of dermatomyositis and polymyositis should have had age appropriate cancer screening.
  • 3) Iodine is found in many foods including seaweed, kelp, certain medications (eg amiodarone) and in contrast agent. A person with a normal thyroid should be able to regulate excess exogenous iodine intake but someone with hypothyroidism may develop clinical hyperthyroidism.

Want to learn more?

Inflammatory myopathies

  • There are 4 main types of inflammatory myopathies, DM, PM, IBM and necrotizing autoimmune myositis.
  • Key features pre-biopsy/ testing of each include:
    • DM – characteristic skin rash
    • PM – usually diagnosis of exclusion
    • IBM – distal muscle weakness with atrophy of hand muscles
    • NAM – very high CK levels
  • Treatment of dermatomyositis and polymyositis generally consists of steroids. Refractory disease may benefit from rituximab and IVIG.

Here is a great chart from an NEJM review article on inflammatory muscle disorders.

temp.jpeg

Abnormal TFTs

  • the differential for a high TSH and normal fT4/T3 includes subclinical hypothyroidism, drugs and euthyroid sick syndrome
  • check T3 if someone has clinical hyperthyroidism but normal TSH/T4

Here is an excellent video by Palo Alto VA Internist/ clinician educator Eric Strong on interpretation of abnormal thyroid function tests.

Statin-Induced Autoimmune Myositis

statin.jpg

Today Dr. Peng presented a case of immune-mediated necrotizing myopathy in association with statin therapy which presented with dysphagia for several weeks and a profound CK elevation.

On review, there appears to be a range of statin associated myopathies. Some of these appear to improve with discontinuation of the statin itself. These are likely a result of the direct toxic effect of that statin on muscle tissue. However, others do not improve and follow a pattern more typically seen with immune-mediated necrotizing myopathies which include anti-SRP and paraneoplastic necrotizing myositis. The illness script here includes CK greater than 3k and rapid onset of weakness and/or dysphagia from severe myopathy. There is also and argument to that criteria for dermatomyositis and polymyositis should also be included in this description and would include symmetrical, proximal muscle weakness. However, in statin-induced autoimmune myositis thre is limited or absent inflammation on muscle biopsy. In these individuals, the anti-HMGCoA reductase autoantibody is elevated. This is a rare form of nectrotizing myositis which often requires immunosuppression to alleviate symptoms. Please see the article in Autoimmune Review for more information on statin-induced autoimmune myositis. Some other important considerations are to evaluate for hypothyroidism and vitamin D deficiency as these increase the susceptibility of the individual. Additionally, recommendations are to assess for drug-drug interactions (remember the CYP3A4 enzymes!).

Synthetic cannabinoid overdose

Thanks Rishi Surana for presenting a great case and thanks to Ran Ran for lending his expertise on this subject. This is a young person with a history of Graves disease who was not adherent to thionamide therapy who presented with acute altered mental status found secondary to synthetic marijuana overdose.

temp.jpg

Main Points:

  • 1) The treatment of Graves disease generally consists of 1-2 years of thionamide therapy first to see if remission is achieved. If not, radioactive iodine and surgery are definitive therapies.
  • 2) A urine drug screen is not comprehensive and may be missing items like methadone and does not pick up on synthetic drugs. The chemistry lab and toxicology consults are excellent resources for what to order as well as time after ingestion the test is effective for.
  • 3) Common toxidromes to categorize presenting symptoms of AMS suspected secondary to ingestion into are: sympathomimetic, anticholinergic, cholinergic, sedative-hypnotic and opioid. See this excellent previous post on toxidromes.

Want to learn more?

Thyrotoxicosis

Here is a fantastic overview of diagnosis and management of thyroid emergencies by Ran.

Synthetic cannabinoid use

Here are two excellent NEJM papers Rishi found regarding the rise of synthetic cannabinoid use which discuss the myriad of chemical structures of these drugs far outstripping our ability to test for them in a UDS. One from 2015 is a case series of individuals who had severe adverse events or deaths associated with synthetic cannabinoid use. The other is another case series from 2017 of a group of individuals who used in NYC who looked “zombie” like.

Abdominal Pain, Steroids, Cobicistat and a CYP3A4 Interaction: Adrenal Insufficiency

Today Dr. Gordon presented a case of abdominal pain, vomiting and malaise that was found to adrenal insufficiency presumably from the interaction between cobicistat and recent intra-articular glucocorticoid injection. This was a reminder to monitor for drug-drug interaction and side effect profiles especially with HIV medications.

Many drugs are metabolized via the cyptochrome P450 (CYP3A4) system. Medications utilized to treat HIV infection, particularly ritonavir and cobicistat, are strong inhibitors of the CYP3A4 system. Thus creating the significant potential for drug-drug interactions and side effects. One such interaction is with glucocorticoids and can result in iatrogenic Cushing's syndrome and, at supraphysiologic levels can suppress ACTH and endogenous corticosteroids resulting in secondary adrenal insufficiency. According to a retrospective review published in the Journal of Clinical Medicine in 2016, glucocorticoid excess can occur in hours to days. And, HPA access suppression can occur in as few as 5 days when at relatively high doses. But are more often seen with treatment for 3 weeks or longer. Similarly, glucocorticoids can be administered via any route (inhaled, nasal, intra-articular, epidural, topical, ocular or oral). In considering this drug-drug interaction the following flow-sheet outlines the investigation and management:

Adrenal Insufficiency Table.png

If there is need for a steroid but there is concern for this interaction, the author's suggest the following: use beclomethasone for inhaled or nasal needs (metabolized by esterase hydrolysis and minimal CYP), methylprednisolone for injections with a 30% dose reduction or steroid sparing options. If all those options are unavoidable, consider discussion with the HIV provider to change to a non-ritonavir/cobicistate containing regimen.

Tyramine induced hypertensive emergency

Today, we had a fascinating case presented by Dr. Scharman of an older male with a history of CAD, chronic stable angina, and treatment resistant depression who presented with chest pain, found to have hypertensive crisis. Dr. Scharman gathered additional information and discovered the patient had recently discontinued an MAOI antidepressant and ingested a hardy meal full of aged cheeses and beer. The combination caused a tyramine induced hypertensive crisis that resolved with benzodiazepines.

In thinking about hypertensive crises, there are a few causes to consider including:

  • medication non-adherence
  • CVA/cerebral edema/brain tumor/spinal cord injury
  • eclampsia
  • pain
  • burns
  • hyperadrenergic drugs (cocaine, amphetamines, PCP, MAOIs)
  • abrupt medication discontinuation (i.e. clonidine and beta blockers)

Dr. Scharman reviewed the pathophysiology of why MAOIs (with ingestion of aged cheeses) can cause hypertensive crises.

During aging, proteins in cheese are broken down via bacteria to form peptides and free amino acids.  Some of these bacteria produce amines such as tyramine.  Usually the high concentration of MAO in the intestinal mucosa breaks down excess tyramine in the body.  However, the use of MAOIs inhibit this activity, and thus tyramine can build up.  This "pressor" amine can then lead to hypertensive crisis.

During aging, proteins in cheese are broken down via bacteria to form peptides and free amino acids.  Some of these bacteria produce amines such as tyramine.  Usually the high concentration of MAO in the intestinal mucosa breaks down excess tyramine in the body.  However, the use of MAOIs inhibit this activity, and thus tyramine can build up.  This "pressor" amine can then lead to hypertensive crisis.

Dr. Schmarman's Learning Points:

  • Medication reconciliation should always include recently discontinued medications.
  • At least 2 weeks must elpase after discontinuing MAOIs before starting another antidepressant or stopping the MAOI diet.
  • Treatment of hypertensive crisis related to tyramine + MAOIs is benzodiazepines. Avoid beta blockers due to unopposed alpha.
  • Symptoms related to abrupt discontinuation of MAOIs can occur, typically seen with higher risk of symptoms in those who abuse the medication and those with longer duration of treatment at higher doses.