Thank you, Hailen, for presenting a case of an older woman with ESRD on PD who presented with a week of progressive pain in her bilateral calves, found to have very tender subcutaneous nodules on exam, a calcium-phosphorus product of ~75, and imaging findings of calcium deposition in the arteries and subcutaneous tissue – putting it all together, concerning for calcemic uremic arteriopathy!
- The differential diagnosis for subcutaneous nodules is extensive! Starting with a framework to break down categories of disease can be useful, such as primary inflammatory causes, infectious causes (both direct infection and via distant immunephenomena), benign causes, and malignant causes.
- Calciphylaxis, now called calcemic uremic arteriopathy is a rare disorder associated with ESRD patients that leads to skin ischemia and necrosis. See more below!
Calcemic Uremic Arteriopathy – check out this 2014 review for more details
- Thought to develop due to disruption of balance between factors favoring calcification and those preventing pathologic calcification
- Likely a combination of passive mineralization in setting of high calcium-phosphorus product, as well as abnormal active cellular processes
Hallmarks of Disease:
- Vasculopathy with extensive medial calcification
- HIGH risk of cardiovascular mortality
Risk Factors: #1 CKD/ESRD
- Demographics: Female sex, white race
- Comorbidities: Diabetes mellitus, Obesity, Secondary hyperparathyroidism
- Labs: Calcium-phosphate product > 70, Low serum albumin, Elevated AlkPhos, Protein C and/or S deficiency
- Time on HD
- Medications: Vitamin D supplementation, Calcium-based phosphate binders, warfarin, corticosteroids, iron dextran, erythropoietin,
- Often initially present as excruciatingly painful subcutaneous nodules with violaceous mottling, similar to livedo reticularis. Lesions generally progress to forming ulcers and eschars as a result of ischemic necrosis.
- Main body areas affected are those with higher fat concentrations: breast, abdomen, thighs, hips.
- Secondary infection VERY common
- Often made clinically, though histopathology is considered the gold standard.
- Medial calcification of small arteries and arterioles with intimal hyperplasia, inflammation, endovascular fibrosis, thrombosis and tissue necrosis. Panniculitis can also be present.
- However, biopsy does raise concern for initiating a new ulcer that may not heal!
- Take home: biopsy when clinical picture is not clear in order to rule out other diagnoses such as warfarin-induced skin necrosis, vasculitis, cholesterol embolism syndrome, nephrogenic systemic fibrosis
- Other diagnostic modalities include:
- Bone scintography – sensitivity of 97% in detecting abnormal calcifications
Treatment (from the 2014 review by Yerram and Chaudhary linked above):
Thank you, Claire, for presenting a case of a young man who presented with acute abdominal pain found to have appendicitis and DKA from profound hypertriglyceridemia!
- The differential diagnosis for labs that cannot be calculated include substances in the blood that are interfering with tests, commonly fats, proteins, and bilirubin.
- The management of hypertriglyceridemia induced acute pancreatitis (HTG-AP) includes: IVF, bowel rest, insulin, pain control, electrolyte management and, in extreme circumstances, plasmapheresis!
- In patients with an underlying metabolic defect, the common triggers that can result in profound hypertriglyceridemia (and resultant complications) include development of glucose intolerance, alcohol use, and thyroid dysfunction.
Check out this awesome post from Anna Parks also about hypertriglyceridemia and pancreatitis! She reviews the many causes of endogenous and exogenous substances that can cause lab interference, genetic causes of hypertriglyceridemia, and treatment.
More on plasmapheresis for treatment of HTG-AP
In this systemic review of HTG-AP, the authors found 8 studies that evaluated plasmapheresis as a specific treatment for HTG-AP. All 8 studies concluded that plasmapheresis is an effective treatment for reducing serum triglyceride concentration. Two studies found that symptoms of acute pancreatitis, particulary abdominal pain, were also improved. In patients with chronically elevated triglycerides, 2 studies found that long-term, routing plasmapheresis decreased recurrence of HTG-AP. In summary, the authors concluded that the treatment does not seem to decrease the morbidity and mortality of HTG-AP. However, prospective, randomized trials are needed!
This treatment seemed to work magic for Claire’s patient! Here’s a photo of the fat that was apheresed from her patient’s blood.
Thank you to our hospitalist, Sarah Apgar, for joining us today! Sarah presented a case of an elderly woman originally from China with several months of recurrent fevers eventually found to have sputum AFB smear negative, PCR positive consistent with underlying mycobacterium tuberculosis infection.
- FUO is defined as document fevers to 38.3 following the rule of 3s: duration >3 wks AND no clear explanation after >3 outpatient visits OR >3d in hospital.
- Majority of FUO cases fall into 3 buckets: 1) Infections 2) Non-infectious inflammatory disease 3) Malignancy (classic!) – see below for more details on prevalence.
- Patience is a virtue – up to 40-50% of FUOs resolve on their own with NO UNDERLYING DIAGNOSIS ever determined!
- In addition to microscopic polyangitis and eosinophilic granulomatosis with polyangitis, MPO antibodies can be seen in patients with chronic infections – including TB.
- IDSA guidelines recommend using MTB-PCR testing in addition to AFB smear and culture for patients with suspected TB. In today’s world, you should not “rule out” TB without MTB-PCR! (more below about the data!)
Fever of unknown origin (FUO):
- Definition: rule of 3s!
- T >38.3
- >3 weeks as an outpatient OR
- Unrevealing w/u after >3 outpatient visits or >3 days in the hospital
- Majority of cases fall into the following 3 large buckets:
- Infectious: HIV, fungal, atypical, mycobacterial, parasite, osteomyelitis, endocarditis, abscesses (liver)
- Malignancy: hematological (leukemia) vs. solid (lymphoma, RCC, HCC)
- Inflammatory: giant cell arteritis, Sarcoid, Behcets, Stills, other vasculitis
- Other: clot, drug/meds, hematoma, central dysregulation – pheo, thyroid disease, IL-2 mediated
- Start with complete history and physical exam.
- Minimum diagnostic evaluation should include: blood cultures, erythrocyte sedimentation rate or C-reactive protein, serum lactate dehydrogenase, HIV antibody test and viral load, rheumatoid factor, heterophile antibody test, creatine phosphokinase, antinuclear antibodies, interferon-gamma release assay, serum protein electrophoresis, and computed tomography scan of abdomen and chest.
Epidemiology of FUO
The epidemiology of FUO has changed over time. With advances in diagnostic tools, we have been able to diagnose a growing myriad of diseases more quickly. As a result, the proportion of FUOs that go without a diagnosis has dropped from ~80% in the 1920-1930s to 40-50% more recently.
A large study published in 2007 in the Netherlands of immunocompetent patients found the following distribution of causes:
- Noninfectious inflammatory causes – 22%
- Infection – 16%
- Malignancy – 7%
- Other – 4%
- No diagnosis – 51%
Sensitivity of MTB-PCR versus 2 or 3 AFB Smears
From Anne Luetkemeyer’s 2016 Clinical Infectious Disease paper, we have learned that MTB PCR significant increases sensitivity for detecting TB in US patients with AFB smear negative sputum.
- Sensitivity of 2 MTB PCR is 100% in smear positive patients & 70% in smear-negative x3 patients à MTB PCR enables us to identify a significant portion of smear negative patients that otherwise would not have been identified until after MTB culture
Thank you, Lily, for presenting a case of an older woman reporting several weeks of painful anterior neck and throat, signs of hyperthyroidism on exam, found to have subacute thyroiditis (antibodies still pending)!
1) Thyroiditis refers to inflammation of the thyroid – there are many potential causes to this – see below for a full DDx.
2) A painful thyroid can considerably narrow your differential – the 4 causes that are associated with spontaneous pain include non-Hashimoto autoimmune thyroiditis, suppurative thyroiditis, trauma-related, post-radiation thyroiditis. Both Hashimoto and Graves are typically painless.
3) The pathophysiology Graves thyrotoxicosis and Hashimoto thyroiditis originate with aberrant T-cell activity. One can really think of these disease as a spectrum rather than two distinct conditions given the overlap in pathophys and shared genetic predisposition.
Classification of Thyroiditis (adapted from AAFP.org – linked to a GREAT article by Slatosky, Shipton, and Wahba)
Thank you, Lily, for presenting the case of an older woman with dementia, Fahr disease, and diabetes presenting with AMS.
- Fahr disease is a rare neurodegenerative condition characterized by accumulation of calcium deposits in the basal ganglia that results in movement disorder and cognitive impairment. See below for more!
- The most common cause of hypercalcemia in the hospitalized patient is underlying malignancy.
- Remember the Cl:Ph ratio can help suggest if hypercalcemia is PTH dependent or independent. A ratio <35 suggests PTH independent, but AKI can make this a bit difficult to interpret – if fluids resolve your AKI, recheck the ratio!
What the heck is Fahr disease?
- Fahr disease AKA idiopathic basal ganglia calcification (IBGC) AKA bilateral striopallidodentrate calcinosis
- Rare neurodegenerative condition characterized by accumulation of calcium deposits in the basal ganglia.
- Clinical signs and symptoms vary, but include parkinsonism, chorea, dystonia, cognitive impairment, and ataxia.
- In addition to the idiopathic variant, there is an autosomal dominant inherited form, known as primary familial brain calcification (PFBC).
- Interestingly, IBGC and PFBC are not associated with disorders of calcium or PTH metabolism.
- If you want to learn more, here is a description of sporadic and familial cases in a registry of patients. The authors note that the amount of calcification seen on brain CT seems to correlate with the severity of symptoms. Movement disorders were the most common manifestations of the disease, and among movement disorders, parkinsonism in particular.
Hypercalcemia Review – here’s an approach based on the PTH: